Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 8, pp. 1319-1340 © Pleiades Publishing, Ltd., 2026.

ISSN 0006-2979, Biochemistry (Moscow), 2026. © Pleiades Publishing, Ltd., 2026.

1319

REVIEW

Diabetic Retinopathy:

From Molecular Mechanisms to Modern Therapy

Natalia G. Shebardina

1,a

*, Kristina A. Kazakova

2,3,b

, Timur A. Asaevich

1,4,c

Sofia A. Belolipskaia

1,4,d

, Ivan V. Rodionov

5,6,7,e

, Sanchay S. Tulush

1,5,f

Mikhail L. Shishkin

1,5,g

, Andrey R. Komarov

8,h

, Olga A. Krasienko

9,i

Elizaveta S. Gromova

10,j

, Andrey A. Zamyatnin Jr.

1,5,6,k

Anastasia M. Moisenovich

1,2,l

, and Evgeni Yu. Zernii

1,m

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University,

119992 Moscow, Russia

Faculty of Biology, Lomonosov Moscow State University, 119992 Moscow, Russia

Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119992 Moscow, Russia

Department of Biotechnology, Nelyubin Institute of Pharmacy,

Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation,

119991 Moscow, Russia

Department of Biochemistry, Institute of Digital Biodesign and Artificial Intelligence in Medicine,

Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation,

119991 Moscow, Russia

Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University,

119992 Moscow, Russia

Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University,

Ministry of Health of the Russian Federation, 119991 Moscow, Russia

Center for Master's Degree Programs, Institute for Regenerative Medicine,

Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation,

119991 Moscow, Russia

Faculty of Chemical Technology and Biotechnology, Moscow Polytechnic University,

107023 Moscow, Russia

Faculty of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia

e-mail: natuskasheb@gmail.com

e-mail: krkan7@mail.ru

e-mail: timurasaevich@mail.ru

e-mail: sofiya.belolipskaya@list.ru

e-mail: ivan1rodionov@gmail.com

e-mail: sanchai2003@mail.ru

e-mail: mikhshishkin@gmail.com

e-mail: 1stefanswe1@gmail.com

e-mail: olga.krasienko@yandex.ru

e-mail: gromova@belozersky.msu.ru

e-mail: zamyat@belozersky.msu.ru

e-mail: a-moisenovich@mail.ru

e-mail: zerni@belozersky.msu.ru

Received April 1, 2026

Revised April 27, 2026

Accepted April 27, 2026

Abstract— Diabetic retinopathy (DR) remains one of the leading causes of vision loss. Its development is

driven by complex interconnected pathophysiological mechanisms triggered by chronic hyperglycemia.

Traditional diagnostic approaches, which rely on detecting visible microangiopathies, often identify the

disease only after significant and progressive retinal damage had already occurred. Consequently, current

therapeutic strategies are largely focused on managing advanced, proliferative stages of DR. A major direc-

tion in modern ophthalmology is the shift toward identifying and intervening at stages that precede clin-

ical DR manifestations. This review presents current data on the pathogenesis and molecular mechanisms

of DR, discusses associated biochemical alterations revealed through multi-omics approaches, and examines

* To whom correspondence should be addressed.

SHEBARDINA et al.1320

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

methods for preclinical diagnostics, innovative therapeutic strategies, and novel targets for early pathoge-

netic intervention. Overall, the evidence suggests that that effective treatment options for DR might include

multi-target therapeutic approaches extending beyond the blockade of angiogenesis and aimed at address-

ing metabolic, inflammatory, and oxidative disorders causing neurodegeneration and vascular dysfunction.

DOI: 10.1134/S000629792660105X

Keywords: diabetic retinopathy, molecular mechanisms, early diagnosis, biomarkers, pathogenetic treatment,

preclinical stage

INTRODUCTION

Definition and epidemiology. Diabetic retinop-

athy (DR) is a disabling neuromicrovascular compli-

cation of diabetes mellitus (DM), regardless of type,

driven primarily by chronic hyperglycemia. The risk

of developing  DR in patients with  DM directly de-

pends on glycemic control, disease duration, genetic

predisposition, and the presence of concomitant con-

ditions that exacerbate retinal hypoxia and endothe-

lial damage (atherosclerosis, arterial hypertension,

pregnancy, nephropathy, anemia)  [1,  2]. According to

a 2020 global meta-analysis, one in five of individu-

als with DM worldwide (22.3% of all DM patients) is

affected by  DR. Among these, the prevalence of pro-

liferative stage is 6.17%, while diabetic macular ede-

ma (DME) occurs in 4.07% of patients  [3]. According

to 2016 data, the incidence of DR in the population

of the Russian Federation is 38.3% for patients with

type  1  DM and 15.0% for patients with type  2  DM,

with the proliferative form accounting for 12.1% and

5.8% of cases, respectively  [4]. These epidemiological

findings emphasize the substantial medical and so-

cial significance of DR as one of the main causes of

vision loss.

DR classification and morphological changes in

the retina. The classification proposed by the Early

Treatment Diabetic Retinopathy Study (ETDRS) Re-

search Group (1991) remains widely accepted in clin-

ical practice  [5]. It distinguishes three stages of DR:

non-proliferative, pre-proliferative, and proliferative

(DME is typically considered a separate, vision-threat-

ening complication that may develop at any stage of

DR). Pathological changes at the non-proliferative di-

abetic retinopathy (NPDR) stage include pericyte de-

generation, increased capillary permeability, and the

formation of microaneurysms, which can later lead

to retinal edema and visual impairment. The pre-pro-

liferative stage (PPDR, R2, or severe NPDR) is char-

acterized by the appearance of vascular anomalies

without evidence of neovascularization. Proliferative

diabetic retinopathy (PDR) is accompanied by disrup-

tion of the blood–retinal barrier (BRB) and reduced

perfusion pressure in the retinal vessels, which trig-

ger neovascularization often resulting in severe and

irreversible retinal damage. The primary causes of

vision loss in DR are DME and proliferative form

of the disease. Although DME can occur at any DR

stage, the likelihood of its development increases as

retinal changes progress, reaching 71% in patients

with PDR  [6].

Main events of DR pathogenesis. DR is charac-

terized by a multifactorial nature of lesions; however,

its major trigger is hyperglycemia which initiates a

cascade of interconnected pathological processes that

ultimately result in the retinal tissue damage. The

main targets of high glucose levels are insulin-inde-

pendent neuronal and endothelial cells, where the

earliest pathological changes take place. A key pro-

cess occurring at the early preclinical stage of the

disease is oxidative stress, which disrupts epigenetic

regulation and promotes neurodegeneration  [7-9]. The

principal pathogenic mechanisms in NPDR include

chronic sterile inflammation and associated vascular

dysfunction  [10,  11]. Leukocyte adhesion to the vascu-

lar endothelium leads to capillary occlusion followed

by the damage to endothelial cells and pericytes  [12].

Pericytes are essential for maintaining vascular wall

integrity, regulating permeability, and controlling lo-

cal blood flow; their loss leads to structural instability

of newly formed vessels, thus increasing susceptibility

to hemorrhage and retinal ischemia. These microcir-

culatory disturbances are further aggravated by the

hyperglycemia-induced procoagulant state  [13,  14].

In parallel, elevated glucose levels impair blood rheol-

ogy, exacerbating tissue hypoxia. As NPDR progresses

to more advanced stages, including PPDR, the damage

to the BRB becomes evident. Inflammation and oxi-

dative stress lead to destabilization of tight junction

proteins such as occludin (OCLN), claudin (CLDN),

and zona occludens-1 (ZO-1), resulting in increased

vascular permeability and damage to the retinal pig-

ment epithelium (RPE), another critical component

of the BRB  [15,  16]. In PDR, pathological angiogene-

sis predominates, leading to extravasation of blood

components with subsequent growth of connective

tissue  [17]. The latter tends to retract, and the fibro-

vascular complex adheres to the posterior hyaloid

membrane, which can lead to vitreous body detach-

ment. Neovascular formations can rapture, resulting

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1321

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

in preretinal or vitreous hemorrhages. Recurrent

bleeding and scarring of the vitreous body posteri-

or segments form pathological vitreoretinal tractions,

contributing to retinal detachment. Additionally, neo-

vascularization may extend to the iris (rubeosis iridis)

or the area of the anterior chamber angle, provoking

neovascular glaucoma  [18].

Treatment strategies and associated challeng-

es. Modern therapeutic strategies for DR are still

largely directed at managing it advanced stages rath-

er than preventing the onset or early progression.

Laser coagulation of the retina (panretinal photoco-

agulation, PRP) is primarily indicated for PPDR (as

a relative indication) and PDR, while vitreoretinal

surgery is reserved for complicated PDR cases, such

as those involving hemophthalmos, tractional retinal

detachment, or macular traction, with the goal of

restoring normal retinal anatomy  [19]. Pharmacolog-

ical treatment options remain limited to the use of

vascular endothelial growth factor (VEGF) inhibitors,

including aflibercept, faricimab, and ranibizumab.

Ranibizumab is available both as an intravitreal in-

jection and as a component of the Susvimo implant,

which is surgically embedded in the sclera of patients

who have demonstrated responsiveness to anti-VEGF

therapy. These agents are indicated for PDR and DME

at any stage  [20]. However, approximately 30-40% of

patients exhibit a suboptimal response or develop re-

sistance during prolonged treatment, diminishing the

overall efficacy  [21]. The key problem with the Susvi-

mo implant is a higher incidence of endophthalmitis

compared to monthly intravitreal injections of ranibi-

zumab. In addition, anti-VEGF therapy entails higher

costs compared to PRP, despite yielding comparable

clinical outcomes  [22]. In DME patients with inad-

equate response to anti-VEGF therapy, intravitreal

corticosteroids may be employed. However, their use

is limited by pronounced adverse effects, including

cataract formation and elevated intraocular pressure

(IOP)  [23]. Despite demonstrated clinical effectiveness,

the described treatment strategies primarily address

complications of already developed disease, leaving

the problem of early DR therapy unresolved.

Current state of research. The number of scien-

tific works on DR has been growing rapidly in recent

years, reflecting the relevance of the problem. As of

2025, major bibliometric databases contained nearly

70,000 publications dedicated to this topic, which sub-

stantially exceeded the number of studies devoted to

many other retinal vascular diseases  [24]. Research

activity has been particularly intense in the past de-

cade: by 2023, the annual global output surpassed

400 publications  [25]. The number of reviews on DR

is also steadily growing; many of them are mentioned

in this article. Most of these reviews focus on one of

the five key topics: epidemiology and classification;

diagnostics and imaging; therapeutic strategies and

drug delivery systems; molecular mechanisms; and

genetics/epigenetic regulation. In contrast, the pres-

ent work aims to integrate these areas within a sin-

gle framework, offering a concise yet comprehensive

overview of the current state of DR research. Particu-

lar emphasis is placed on linking established concepts

on molecular pathogenesis and signaling pathways in

DR with emerging findings from biochemical studies

using patient-derived materials, especially those gen-

erated using advanced high-throughput omics tech-

nologies.

MOLECULAR MECHANISMS

OF RETINAL DAMAGE INDR

Hyperglycemic conditions lead to non-enzymatic

glycation of proteins, lipids, and nucleic acids, result-

ing in the accumulation of advanced glycation end

products (AGEs). In the Maillard reaction, carbonyl

groups of sugars react with amino groups to form

unstable Schiff bases, which subsequently rearrange

into more stable Amadori products. Through further

oxidation and dehydration, these intermediates gen-

erate reactive dicarbonyl compounds that modify

lysine and arginine residues in proteins, promoting

cross-linking and the formation of stable AGEs  [26].

It is believed that the main factors causing transi-

tion from chronic hyperglycemia to structural and

functional changes characteristic of DR are oxidative

stress, neuroinflammation, and vascular dysfunction,

followed by neurodegeneration and neovasculariza-

tion (Fig.  1).

Oxidative stress. The binding of AGEs to their

receptors (RAGEs, advanced glycosylation end prod-

uct-specific receptors) on the surface of vascular

cells (endotheliocytes, pericytes) and retinal neurons

triggers generation of reactive oxygen species (ROS)

through the activation of RAC1 (Ras-related  C3 botu-

linum toxin substrate  1), NOX (NADPH oxidase), and

PKC-δ (protein kinase  C delta type)  [26-28]. Inaddition,

increased glucose flux through glycolysis causes an

overload of the mitochondrial respiratory chain, lead-

ing to impaired electron transport at complex III and

superoxide production. This results in the excessive

generation of ROS (H

, ·OH, ONOO

−

), which damage

lipids, proteins, and DNA  [29]. Oxidative stress inhibits

the activity of the key glycolytic enzyme glyceralde-

hyde 3-phosphate dehydrogenase (GAPDH), redirecting

glycolytic metabolites to the polyol and hexosamine

pathways  [30]. In the polyol pathway, glucose reduc-

tion to sorbitol is accompanied by the consumption

of NADPH, thereby limiting regeneration of reduced

glutathione (GSH) by glutathione reductase (GR) and

weakening the antioxidant capacity of the cell  [31].

SHEBARDINA et al.1322

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

Fig. 1. Molecular mechanisms underlying development of DR. The formation of AGEs, upregulation of glycolysis, and ac-

tivation of the hexosamine and polyol pathways lead to oxidative stress, osmotic damage, and inflammation, contributing

to the development of early retinal neurodegeneration. In turn, neovascularization and BRB disruption occurring at later

stages exacerbate damage to the neurovascular units.

Accumulation of sorbitol causes osmotic stress to

retinal vascular cells, while its subsequent oxida-

tion generates additional glycating agent (3-deoxy-

glucosone)  [32]. Cellular damage is exacerbated by

the reduced activity of antioxidant defense enzymes,

such as superoxide dismutase (SOD) and catalase

(CAT), as well as decreased levels of non-enzymat-

ic antioxidants (vitamins  C and  E, β-carotene)  [33].

These changes ultimately lead to mitochondrial dys-

function, characterized by swelling, loss of membrane

potential, and increased inner membrane permeabil-

ity. As a result, cytochrome  c is released to the cyto-

sol, inducing caspase-9 and caspase-3 activation and

triggering apoptosis in neurons, endothelial cells, and

pericytes  [34]. Mitochondrial dysfunction is also as-

sociated with impaired calcium homeostasis. In neu-

rons, these disturbances are aggravated by a massive

calcium influx driven by glutamate excitotoxicity  [35].

Together, these processes create a self-perpetuating

cycle of oxidative stress, further promoting mitochon-

drial destabilization, endoplasmic reticulum stress,

and dysregulation of NAD

metabolism  [36].

Inflammation. RAGE activation on the surface

of retinal neurons induces inflammatory processes

in the retina through the signaling pathways mediat-

ed by JAK (Janus kinase)–STAT (signal transducer and

activator of transcription), and ERK1/2 (extracellular

signal-regulated kinase 1/2), PI3K (phosphoinositi-

de  3-kinase)–AKT (protein kinase  B), and Ras (Retro-

virus associated sequences)–Rac–Cdc42 (Cell division

control protein  42), as well as by MAPK (mitogen-ac-

tivated protein kinase) signaling that involves p38

and JNK (c-Jun N-terminal kinase). This results in the

activation of the transcription factors AP-1 (activat-

ing protein-1) and NF-κB (nuclear factor kappa-light-

chain-enhancer of activated B  cells), the latter playing

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1323

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

a key role in DR pathogenesis  [37,  38]. Under oxida-

tive stress, NF-κB is activated by phosphorylation and

subsequent degradation of its inhibitor IκB (inhibitor

of nuclear factor kappa-B)  [38]. In addition, NF-κB ac-

tivity is promoted by oxidative DNA damage and acti-

vation of poly(ADP-ribose) polymerase  1 (PARP1)  [39].

Activated NF-κB upregulates expression of pro-inflam-

matory factors, such as cytokines interleukin-1 beta

(IL1β), tumor necrosis factor-alpha (TNF-α), interleu-

kin-6 (IL6), interleukin-8 (IL8), and C-C motif chemo-

kine (CCL2), as well as cyclooxygenase-2 (COX2), in-

ducible nitric oxide synthase (iNOS), and angiogenic

factors, primarily VEGF  [39-41]. Notably, pro-inflam-

matory cytokines themselves activate NF-κB, creating

an autocrine loop that maintains chronic inflamma-

tion in DR. Activation of the hexosamine pathway by

glutamine:fructose-6-phosphate aminotransferase  1

(GFAT) leads to the accumulation of uridine diphos-

phate-N-acetylglucosamine, which modifies transcrip-

tion factors and induces transforming growth factor

beta-1 (TGF-β1) expression. This contributes to the

extracellular matrix (ECM) remodeling and promotes

inflammation  [42].

At the cellular level, increased cytokine secre-

tion in the retina activates resident microglia and

infiltrating macrophages, inducing their polarization

towards the classical pro-inflammatory M1 pheno-

type  [43]. Prolonged activation of M1 microglia exac-

erbates neuroinflammation and leads to the damage

to neurons and glial cells, which are characteristic

signs of early DR stage. In addition, microglia-de-

rives cytokines [TNF-α, FGF2 (fibroblast growth fac-

tor  2), IGF1 (insulin-like growth factor  1)], chemok-

ines [CCL2, CCL3 (C-C motif chemokine  3), CCL5 (C-C

motif chemokine  5), CXCL12 (stromal cell-derived

factor  12)] and growth factors (VEGF) interact with

endothelial cells, stimulate neovascularization, and

upregulate expression of adhesion molecules, such

as ICAM1 (intercellular adhesion molecule  1) and

VCAM1 (vascular cell adhesion protein  1), facilitat-

ing leukocyte adhesion (leukostasis) and subsequent

migration into the retina  [44-47]. By secreting ROS,

proteases, and cytokines, leukocytes contribute to

the capillary lumen narrowing, disruption of micro-

circulation, and microvascular inflammation, leading

to retinal ischemia and further upregulation of VEGF.

Collectively, these processes lead to destabilization of

cell–cell contacts, degradation of ECM components,

and pericyte apoptosis, ultimately compromising BRB

integrity  [40,  48]. Another mechanism of BRB dam-

age involves increased expression of angiopoietin-2

(ANGPT2) in pericytes and endothelial cells under

hyperglycemic conditions. This process is initiated by

pro-inflammatory cytokines and hypoxia-inducible

factor 1-alpha (HIF1A), which activates apoptosis of

these cells through integrin α3β1/p53  [49]. As an an-

tagonist of the angiopoietin-1 receptor (TIE2), ANGPT2

also disrupts endothelial tight junctions, thus increas-

ing vascular permeability and promoting edema for-

mation  [50]. Overall, neuroinflammation represents

an integrative process linking metabolic dysfunc-

tion, oxidative stress, and excitotoxicity, ultimately

leading to neuronal apoptosis and loss of synaptic

contacts.

Neurodegeneration. While the loss of pericytes

and endothelial cells is characteristic mainly of NPDR

and PrePDR, neuronal death and glial activation occur

across all disease stages, including both before the

onset of and during the vascular damage  [51]. The

cytotoxic mechanisms described above affect near-

ly the entire retinal neuronal population, including

photoreceptors, amacrine cells, and ganglion cells, as

well as astrocytes and Müller glia (Fig.  2). Given an

extremely limited regenerative potential of neurons,

their apoptotic death entails irreversible loss of visual

functions. Ganglion and amacrine cells are particular-

ly vulnerable to diabetes-associated stress. Already in

the early stages of the disease, these cells express the

pro-apoptotic factors BAX (Bcl-2-associated X protein),

caspase-3, and Fas (CD95)  [52]. Incontrast, pronounced

degeneration of photoreceptors is more characteristic

of late-stage PDR, although damage to these cells may

begin much earlier  [53]. Under hyperglycemic condi-

tions, rhodopsin expression is reduced, indicating in-

creased vulnerability of these cells to metabolic stress.

Concurrently, de  novo lipogenesis is activated through

the induction of fatty acid synthase, which disrupts

the retinoid cycle and promotes accumulation of sat-

urated lipids, impairing synaptic transmission and

neurovascular coupling  [54]. Notably, photoreceptors

themselves promote metabolic and oxidative stress,

increase BRB permeability, and enhance inflammatory

response in DR. Due to the high content of mitochon-

dria, photoreceptors serve as an essential source of

ROS, as well as produce pro-inflammatory molecules,

including cytokines [IL1β, IL1α (interleukin-1 alpha),

TNF-α], chemokines [CCL2, CXCL1 (stromal cell-derived

factor  1), CXCL25 (stromal cell-derived factor  25)], ad-

hesion molecules (ICAM1), and vascular factors  [55].

Important components of retinal degeneration

in DR are Müller cells (MCs), which act as effectors

of neuroinflammation, vascular dysfunction, and fi-

brosis. Under hyperglycemic conditions, they become

activated and produce a broad array of pro-inflam-

matory cytokines [IL1β, TNF-α, IL6, CCL2, IL17 (in-

terleukin-17)], adhesion molecules (VCAM1, ICAM1),

chemokines (CCL2, CCL3), VEGF, and regulatory mi-

croRNAs, which sustain chronic inflammation and

BRB dysfunction and contribute to pathological angio-

genesis  [56]. MCs participate in the induction of exci-

totoxicity, since in diabetes, they lose their capacity to

efficiently clear extracellular glutamate and convert

SHEBARDINA et al.1324

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

Fig.  2. Cellular targets of DR. Retinal damage at different disease stages is shown (normal  →  NPDR  →  PDR). Pathogenetic

factors dominating at different DR stages are described on the bottom left; involved cell types are indicated on the bottom

right. Abbreviations: NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer, INL, inner nuclear layer;

OPL, outer plexiform layer; ONL, outer nuclear layer; PR, photoreceptor layer; RPE, retinal pigment epithelium; Ch, choroid.

The principal protein mediators of the pathological process and cells producing them are shown on the top right.

it to non-toxic glutamine via glutamine synthetase

(GS)  [57]. At the late DR stages, MCs exhibit abnor-

mal proliferation and transdifferentiation into myo-

fibroblasts, becoming the main source of fibroprolif-

erative tissue in the epiretinal space and increasing

the risk of tractional retinal detachment  [58]. Finally,

MCs themselves are targets of DR, since their viability

is impaired by DR-induced expression of TRIB3 (trib-

bles homolog  3), which disrupts glucose metabolism

through activation of HIF1A and transporter GLUT1

(solute carrier family  2, facilitated glucose transporter

member  1) and fibrosis via activation of EGFR (epi-

dermal growth factor receptor)  [59]. Astrocytes also

can be the target of DR. These cells maintain integrity

of the retinal vascular network through direct inter-

actions with the endothelium. In DR, the density of

astrocytes in the retina decreases, i.e., apoptosis of

these cells can mediate early vascular leakage, lead-

ing to initial BRB destabilization  [60].

Neovascularization. VEGF is the principal me-

diator of pathological neovascularization at the late

DR stages. In addition to induction by inflammatory

cytokines (see above), VEGF biosynthesis is triggered

by PKC (protein kinase  C) isoforms  β and  δ, which

are directly activated due to de  novo synthesis of di-

acylglycerol (DAG) under chronic hyperglycemic con-

ditions  [61]. DAG-dependent activation of PKC is also

facilitated by oxidative stress  [7]. Impaired microcir-

culation and retinal ischemia are the major drivers

of VEGF synthesis. Hypoxic conditions lead to the

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1325

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

activation of HIF1A, which induces transcription of

the VEGF gene. Due to alternative splicing, mature

VEGF is represented by four isoforms (VEGF-121,

VEGF-165, VEGF-189, and VEGF-206), which differ

in the presence and length of ECM-binding sites

and, consequently, the range of action  [62]. Thus,

VEGF-121 is freely diffusible and produces systemic

effects, while VEGF-165 (the predominant isoform) is

partially ECM-bound and stimulates survival, prolifer-

ation, and migration of endothelial cells, thus playing

a central role in both physiological and pathological

angiogenesis. Incontrast, VEGF-189 and VEGF-206 are

almost completely sequestered to the ECM, serving

as reservoir for the growth factor that is mobilized

through proteolytic cleavage of ECM-binding sites  [62,

63]. The binding of VEGF to VEGFR2 (vascular endo-

thelial growth factor receptor  2) triggers two signaling

cascades. The first one is mediated by PI3K–AKT and

leads to the inactivation of apoptotic proteins BAD

(bcl2-associated agonist of cell death) and caspase-9

promoting survival of endothelial cells, while also ac-

tivating endothelial NOS (eNOS) and thereby stimu-

lating vascular permeability and vasomotor tone  [64].

The second pathway, mediated by Ras–Raf–MAPK–

MEK–ERK1/2 and transcription factors AP-1 and MYC

(myc proto-oncogene protein), stimulates proliferation

and migration of endotheliocytes  [64]. The pro-angio-

genic effects of VEGF are counterbalanced by the ac-

tivity of its antagonist PEDF (pigment epithelium-de-

rived factor), which directly competes with VEGF for

binding with VEGFR2, reduces VEGF expression by

suppressing HIF1A activity, and activates apoptosis

of endotheliocytes  [65].

IGF1 also plays a pivotal role in neovasculariza-

tion, and its levels are elevated in diabetes. By ac-

tivating insulin-like growth factor  1 receptor (IGF1R)

and the PI3K–AKT–HIF1A signaling pathway, IGF1

promotes VEGF expression, downregulates tight junc-

tion proteins such as CLDN1, and induces the bio-

synthesis of adhesion molecules (e.g., ICAM1). These

effects enhance leukostasis and contribute to chronic

inflammation  [66,  67]. At the same time, IGF1 is crit-

ical for the survival of photoreceptors and ganglion

cells and, in general, demonstrates pronounced neu-

roprotective and reparative properties. It suppresses

neuronal apoptosis through modulation of the same

IGF1R–PI3K–AKT–HIF1A pathway and inhibition of

caspase-3 activity  [68,  69]. Furthermore, IGF1 is a

key factor in reprogramming glial MCs into precur-

sor cells, thereby initiating retinal repair  [70]. The

multidirectional effects of IGF1 are consistent with

its systemic levels in patients. While DR progression

in individuals with DM is associated with decreased

IGF1 levels, an increased risk of developing PDR

correlates with elevated systemic IGF1 concentra-

tions  [71,  72].

REGULATION OF GENE EXPRESSION IN DR

Epigenetic regulation. Epigenetic modifications

play an important role in the pathogenesis of DR,

linking genetic predisposition with metabolic dys-

regulation. As noted above, oxidative stress is a key

trigger of disruptions in epigenetic regulation [7-9].

In hyperglycemia, increased ROS levels upregulate

expression and activity of DNA (cytosine-5)-meth-

yltransferase  3B (DNMT3B), thus promoting hyper-

methylation of the PLTP gene and contributing to

the development of vascular dysfunction through

activation of the AKT–GSK3β (glycogen synthase ki-

nase-3 beta) signaling pathway. Hypermethylation of

the FBW7 gene observed in patients with PDR, reduc-

es expression of the corresponding protein product

and stimulates neovascularization  [73,  74]. Beyond

DNA methylation, additional regulatory mechanisms

involve histone modifications (acetylation and meth-

ylation), which influence the transcription of genes

associated with inflammation, angiogenesis, and ox-

idative stress. Thus, disruption of the activities of

histone acetyltransferase (HAT) and histone deacety-

lase (HDAC) exacerbates vascular dysfunction and

retinal neurodegeneration  [75]. Increased activity of

branched-chain-amino-acid aminotransferase (BCAT1)

in MCs, characteristic of PDR, leads to excessive uti-

lization of α-ketoglutarate. Depletion of α-ketogluta-

rate induces the accumulation of the activating mark

H3K4me3 (trimethylation of lysine  4 of histone  H3)

in the promoters of inflammatory genes  [76]. In ad-

dition, enhanced lactate production under hypergly-

cemic conditions leads to lactylation of histones and

non-histone proteins, driving inflammation, patholog-

ical angiogenesis, and fibrosis  [77].

Translational regulation (microRNAs). Several

microRNAs act as post-transcriptional regulators of

inflammation, pathological angiogenesis, and neuro-

degeneration. Changes in their expression are closely

related to the DR progression  [78]. Thus, an increase

in the level of miR-21, which induces neovascular-

ization through targeting PTEN and activation of

the PI3K–AKT–VEGF pathway, has been consistently

reported in the blood of DR patients. At the same

time, such individuals demonstrated a decrease in

the endothelium-specific miR-126, which exacerbates

vascular dysfunction through reduced expression of

VEGFR2, impaired migration of endothelial cells, and

promotion of their apoptosis, as well as a reduction

in the levels of miR-146, which contributes to in-

flammation through negative regulation of NF-κB via

suppression of IRAK1, TRAF6, and CARD10 [79-81].

Other changes include a decrease in the content of

miR-20b and miR-106b, both of which produce a pro-

nounced anti-angiogenic effect by suppressing VEGF

expression [82-84]. Lower expression of miR-542-5p

SHEBARDINA et al.1326

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

and miR-451a has been observed, alongside elevat-

ed levels of miR-122, which induces apoptosis of ret-

inal cells through the regulation of CARM1, ATF2,

and TIMP3, respectively  [85-87]. Interestingly, certain

protective microRNAs could be upregulated, such as

miR-148a-3p, which reduces BRB damage and sup-

presses angiogenesis by targeting TGFB2 and FGF2,

possibly as a compensatory response [88]. Beyond

microRNAs, long non-coding RNAs (lncRNAs) may

be involved in the pathogenesis of DR; for example,

lncRNA VIM-AS1 binds miR-29 and modulates apopto-

sis of RPE cells [89].

Genetic disorders. A major contributor to the

clinical and phenotypic heterogeneity of DR is its

polygenic architecture, which contrasts sharply with

the Mendelian inheritance patterns typical of most

hereditary ophthalmic disorders  [90]. In DR, the cu-

mulative effect of numerous genetic polymorphisms

generates an overall genetic risk further modulated

by environmental factors  [91]. Genome-wide associ-

ation studies and exome sequencing have identified

several loci associated with susceptibility to DR with

a moderate statistical significance. One of these genes

is AKR1B1, since activation of the corresponding pro-

tein in hyperglycemia promotes sorbitol accumula-

tion, oxidative stress, and microvascular damage to

the retina. The rs9640883 polymorphism is associated

with the risk of developing DR, while the rs759853

polymorphism may exert a protective effect, empha-

sizing the context-dependent contribution of various

AKR1B1 variants to the DR pathogenesis  [92,  93].

An increased risk of developing DR has also been

linked to the insertion/deletion (I/D) polymorphism

of the ACE gene encoding angiotensin-converting

enzyme (ACE), a key component of the renin–an-

giotensin–aldosterone system  [94]. Polymorphisms

of the MTHFR gene, encoding methylenetetrahydro-

folate reductase (MTHFR), affect plasma homocyste-

ine levels and DNA methylation, contributing to the

development of diabetic complications. Specifically,

the rs1801133 (C677T) variant is associated with the

risk of DR in Asian and African populations, while

rs1801131 (A1298C) increases the risk of developing

DR only within the dominant genetic model  [95,  96].

One of the most studied candidates for genetic pre-

disposition to DR is the VEGF gene. Several polymor-

phisms, such as rs699947, rs3025039, and rs833061,

have been associated with increased disease risk,

whereas others, including rs2010963, have shown no

consistent association  [97,  98].

Therefore, the phenotypic diversity observed in

DR is determined by the additive effects of multi-

ple genetic variants with modest individual impacts,

which distinguishes DR from classical monogenic

ophthalmic diseases, thus presenting challenges for

the development of targeted therapeutic strategies.

BIOCHEMICAL CHANGES INDR

In recent years, the rapid development of high-

tech omics methods has enabled comprehensive pro-

filing of low-molecular-weight compounds (metallome,

metabolome, lipidome) and high-molecular-weight

molecules (proteome) and has led to an avalanche-like

growth of data on the biochemical landscape of oph-

thalmic diseases, includingDR. Aparticular relevance

of omics studies of the visual system is related to

the accessibility of biological samples for analysis.

Blood and tear fluid allow assessment of systemic

alterations, while aqueous humor and vitreous body

samples, which can be obtained during routine oph-

thalmic surgeries, provide insight into intraocular

processes [99-101]. In DR, large-scale screenings not

only promote the discovery of novel diagnostic bio-

markers but also facilitate understanding of under-

lying molecular mechanisms (e.g., through lipidomic

and proteomic profiling) and support the develop-

ment of targeted therapeutic strategies.

Metallome. Analyses of patients’ blood have re-

vealed decreased levels of zinc and iron, alongside

elevated copper concentrations, compared with both

healthy controls and individuals with diabetes without

retinopathy[102]. Notably, zinc levels decline progres-

sively with disease transition from the non-prolifera-

tive to the proliferative stage. Zinc deficiency impairs

several protective functions, including antioxidant

activity, as well as suppression of pericyte apoptosis

(via inhibition of caspases) and pathological angiogen-

esis [103]. Excess free copper acts as a potent pro-ox-

idant, promoting lipid peroxidation, damaging cellular

membranes and mitochondria, inhibiting enzymatic

activity, and contributing to protein glycation [102].

Together, these changes markedly promote oxidative

stress, a characteristic feature of DR. In addition, pa-

tients exhibit reduced levels of magnesium and chro-

mium. Chromium deficiency, in particular, may fur-

ther contribute to disease pathogenesis by impairing

normal insulin interaction with its receptor [104].

Metabolome. Systemic alterations in the plasma

metabolome in DR include elevated levels of ribose,

cytidine, thymidine, and other pentose phosphate

pathway intermediates. These changes suggest in-

creased production of NADPH, a critical cofactor for

antioxidant defense mechanisms, reflecting a compen-

satory response to chronic oxidative stress. Among

these metabolites, cytidine has emerged as a promis-

ing diagnostic biomarker ofDR  [105]. More visual sys-

tem-specific localized metabolic disturbances become

evident in the vitreous body. In addition to increased

glucose concentrations, elevated levels of pyruvate

and lactate, along with reduced creatine levels, in-

dicate energy deficit in retinal cells under ischemic

and hypoxic conditions  [105,  106]. Increased ascorbic

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1327

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

acid levels have also been observed in vitreous body

samples, further supporting the presence of oxidative

stress and contributing to the progression of patho-

logical angiogenesis  [105]. Analysis of vitreous body

also reveals disruptions in amino acid homeostasis,

including citrulline, arginine, ornithine, proline, and

branched-chain amino acids (BCAAs), reflecting oxi-

dative stress and endothelial dysfunction  [105-107].

Elevated BCAA levels can activate the mTORC1 sig-

naling pathway, promoting local insulin resistance,

metabolic stress in retinal cells, and upregulation of

VEGF expression  [108,  109]. Multi-omics studies fur-

ther suggest that disturbances in BCAA metabolism

may be linked to mitochondrial dysfunction  [105].

Lipidome. The lipid profile of plasma and oc-

ular fluids in DR is characterized by a pronounced

imbalance in both structural and signaling lipids.

Asthe disease progresses, systemic levels of phospha-

tidylethanolamines, phosphatidylcholines, ceramides,

triglycerides, and sphingomyelins undergo changes,

reflecting deep metabolic reprogramming associated

with insulin resistance, inflammation, and apoptosis

[110,  111]. Elevated levels of sphingomyelins and ce-

ramides indicating the sphingolipid pathway involve-

ment, become evident in the vitreous body lipidome,

in which alterations in the content of phosphatidyli-

nositol, phosphatidylserine, and cholesterol esters are

also observed  [111,  112].

Changes in the signaling lipidome primarily in-

clude an increase in the content of DAG at all stages

of DR, emphasizing the role of PKC activation as a key

molecular mechanism of disease development  [113].

As the pathological process progresses, signs of in-

flammation appear, including decreased levels of

polyunsaturated fatty acids and increased content of

lysophosphatidylcholine, a product of phospholipase

A2 associated with enhanced membrane permeabil-

ity  [114-116].

Proteome. Pathogenetic processes in DR are

also manifested as alterations in the plasma, vitre-

ous body, aqueous humor, and tear fluid proteomes.

In particular, advanced stages of DR are character-

ized by pronounced signs of inflammation, including

increase in the acute-phase proteins alpha-1-antitryp-

sin (AAT), antithrombin-III (AT3), peroxiredoxin-1

(PRDX1), haptoglobin (HP), and C-reactive protein

(CRP), as well as proteins of the classical and alter-

native complement pathways, such as complement  3

(C3) and complement factor  B (CFB)  [117-119]. These

inflammatory changes are also observed in the vit-

reous humor, where increased levels of key pro-in-

flammatory cytokines (TNF-α, IL-6, IL-1) and adhesion

molecules (ICAM-1 and VCAM-1) have been report-

ed  [120,  121]. The proteomic profiles of the vitreous

body and aqueous humor also reflect an imbalance

between angiogenic and anti-angiogenic factors. Spe-

cifically, activation of the PI3K–AKT–HIF1A signal-

ing cascade, which promotes VEGF biosynthesis, has

been documented, along with increased TGF-β1 and

decreased PEDF levels  [120, 122,  123]. Changes in the

proteome of the vitreous body, which is in direct con-

tact with the retina, can reflect neurodegenerative

processes. These include reduced levels of the neu-

ronal injury marker enolase  2 (ENO2) and suppres-

sion of synaptogenesis-related signaling pathways,

such as those involving semaphorin (Sema) proteins

[123,  124]. Additionally, signs of oxidative stress

and endothelial dysfunction are observed, including

elevated dimethylarginine dimethylaminohydrolase  1

(DDAH1) levels  [123]. Several circulating biomarkers

of DR show strong positive associations with DR pro-

gression, including growth/differentiation factor  15

(GDF15), renin (REN), angiopoietin-like protein  4

(ANGPTL4), fatty acid-binding protein  4 (FABP4), and

plexin  B2 (PLXNB2). Increased levels of GDF15, REN,

and FABP4 correlate with thinning of the photore-

ceptor layer, while elevated CES1 (carboxylesterase  1)

is associated with RPE degeneration. Increased hyal-

uronidase-1 (HYAL1) and CCL21 are linked to thin-

ning of the nerve fiber layer, and elevated ADGRG1/

GPR56 (adhesion G-protein coupled receptor G1) and

FGFBP1 (fibroblast growth factor-binding protein  1)

correspond to reduced thickness of the ganglion cell

layer  [125]. A comprehensive summary of proteom-

ic alterations in the vitreous humor, aqueous humor,

plasma, and tear fluid associated with DR is provided

in the Online Resource  1.

In general, the use of omics technologies (metal-

lomics, metabolomics, lipidomics, and proteomics) en-

ables a shift from studying isolated molecular events

to comprehensively mapping biochemical disturbanc-

es underlying DR. Analysis of intraocular fluids of-

fers opportunity to clarify the mechanisms of disease

progression and to identify potential therapeutic tar-

gets. At the same time, detectable alterations in pe-

ripheral blood and tear fluid provide a foundation

for discovering novel biomarkers associated with the

disease onset and progression. Currently, the main

blood-based diagnostic and prognostic biomarkers

of DR include decreased zinc and increased copper

levels, which reflect both disease stage and oxidative

stress. Elevated levels of cytidine and ribose serve as

indicators of systemic metabolic dysregulation, while

increased concentrations of proteins such as GDF15,

REN, and FABP4 represent robust circulating markers

associated with the disease.

EARLY DIAGNOSTICS OFDR

The introduction of modern diagnostic approach-

es has enabled the detection of pathological changes

SHEBARDINA et al.1328

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

even during the preclinical stages of DR  [126]. This

progress has been largely driven by advances in ret-

inal imaging technologies. For instance, ultra-wide-

field imaging now permits visualization of previous-

ly inaccessible peripheral regions of the fundus  [127].

Additionally, techniques for assessing retinal autofluo-

rescence have been introduced, based on detection of

increased intensities in both green and red emission

spectra (GEFC and REFC) in DM patients  [128]. Over-

all, evaluating retinal status in high-risk populations,

particularly, individuals with DM, has become an es-

sential strategy for early DR detection. Modern optical

coherence tomography (OCT) can reveal progressive

thinning of the nerve fiber layer and loss of ganglion

cells well before the onset of clinical symptoms  [129].

Similarly, electroretinography (ERG) can detect func-

tional abnormalities in retinal electrophysiological re-

sponses that often precede clinically evident vascular

changes  [130,  131]. However, the reliability of these

methods is not absolute. Approximately one-third of

patients with detectable microvascular alterations

do not exhibit signs of neurodegeneration in OCT

or ERG  [132]. In this context, significant advances in

data interpretation have been achieved through the

application of artificial intelligence algorithms, which

enhance diagnostic speed, accuracy, and scalabili-

ty and support the implementation of effective DR

screening programs  [133,  134].

An important addition to existing visualization

methods is monitoring of the systemic and local bio-

markers of DR. Among them are universal protein

markers, such as retinol-binding protein  1 (RBP1),

nucleoside diphosphate-linked moiety  X motif  10

(NUDT1), neuroglobin (NGB), which are typically ele-

vated, as well as hemoglobin subunit gamma-2 (HBG2)

and CD160 (cluster of differentiation), which tend to

decrease. Markers reflecting disease risk and severity

include fibroblast growth factor  21 (FGF21), cystatin  C

(CST3), and adiponectin (ADIPOQ). Proteins associat-

ed with inflammation, endothelial dysfunction, and

thrombosis, such as TNF-α, serum amyloid A-1 pro-

tein (SAA1), ICAM1, pentraxin-related protein (PTX3),

S100A12, retinol-binding protein  4 (RBP4), plasmino-

gen activator inhibitor  1 (PAI1), are also implicated.

Neurodegenerative processes may be detected using

neurofilament light chain (NFL) and glial fibrillary

acidic protein (GFAP) as markers  [135-137]. Circulat-

ing microRNAs provide further diagnostic potential.

For instance, miR-126 and miR-21 are associated with

neovascularization. Other markers include miR-181c,

miR-1179, and miR-93, with elevated levels of the

latter correlating to an increased risk of developing

DR in patients with type  2  DM  [138,  139]. Another

promising direction for noninvasive DR diagnosis is

analysis of tear fluid. Due to the ease and minimally

invasive nature of sample collection, this approach is

well suited for large-scale screening. Tear fluid bio-

markers associated with DR include cytokines [IL-6,

IL-8, TNF-α, and MMP9 (matrix metalloproteinase-9)];

other proteins such as insulin-like growth factor-bind-

ing protein  3 (IGFBP3) and progranulin (GRN); neu-

ropeptides, including substance  P and neuropeptide  Y

precursor; as well as lipids, glycosides, microRNAs

(miR-145-5p, miR-214-3p, miR-218-5p, and miR-9-5p),

circular RNAs, and trace elements  [140,  141]. Howev-

er, it is important to note that changes in biomarker

concentrations in plasma and tear fluid may primar-

ily reflect systemic effects of diabetes rather than ret-

ina-specific pathology, which represents a key limita-

tion of these diagnostic approaches.

It can be concluded that expanding diagnostic

strategies to integrated approaches, including ad-

vanced imaging technologies and panels of molec-

ular markers, will enhance the early detection of

DR and enable the timely initiation of preventive

therapy. Focusing on preclinical diagnosis supports

a shift toward disease management at stages when

intervention is both most effective and least costly,

thereby preserving functional reserves of the retina

and maintaining patients’ visual quality. Furthermore,

large-scale prospective studies across diverse popula-

tions, along with standardized pre-analytical proto-

cols, are essential to improve the specificity and reli-

ability of identified biomarkers.

PROSPECTS FOR PHARMACOLOGICAL

THERAPY OFDR

As noted above, current treatment strategies for

DR are largely focused on advanced disease stages,

particularly PDR. Alongside PRP and vitreoretinal

surgery, there is pharmacological management that

is predominantly based on intravitreal administra-

tion of corticosteroids and anti-VEGF agents. While

these therapies are clinically effective, their long-term

application is limited by several important factors,

including the requirement for repeated intravitreal

injections, risk of complications, and the transient

nature of therapeutic response. In this regard, the

development of new delivery systems continues to

ensure prolonged release of active substances, there-

by reducing injection frequency and improving treat-

ment durability, as well as of other combined thera-

peutic strategies aimed at simultaneous modulation

of angiogenic, inflammatory, and neurodegenerative

mechanisms of retinal damage.

Anti-vasoproliferative therapy. Anti-VEGF agents

are a group of diverse molecules, including full-

length monoclonal antibodies, antibody fragments,

and recombinant hybrid proteins  [142]. Although

intravitreal injection remains the standard route

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1329

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

of administration, a range of alternative delivery

strategies has been developed to prolong therapeu-

tic effects, reduce injection frequency, and minimize

treatment-related adverse events  [143]. One approach

involves surgically implanted drug-delivery systems,

such as ranibizumab-containing devices sutured to

the sclera to enable sustained intraocular release.

However, their clinical use is limited by procedure-re-

lated risks, including intraocular hemorrhage and en-

dophthalmitis  [144]. Another strategy employs biode-

gradable aqueous gels based on hydrophilic polymers

capable of high-capacity drug loading and sustained

release over several months  [145]. Particularly prom-

ising are in  situ-forming hydrogels, which are in-

jected as liquids and undergo gelation at the site of

administration in response to physiological triggers

such as temperature or pH  [143]. Polymeric micro-

and nanoparticle systems represent a third strategy.

These biocompatible and biodegradable carriers can

efficiently encapsulate protein therapeutics. For ex-

ample, nanoparticles of poly(lactic-co-glycolic acid

(PLGA) – polyethylenimine (PEI) – 2,3-dimethylmaleic

anhydride (DMMA) triblock copolymer are capable

of pH-responsive surface charge reversal, enhancing

electrostatic interaction with cellular membranes,

promoting endocytosis, and thereby improving in-

tracellular delivery of anti-angiogenic agents  [146].

Liposome-based systems constitute a fourth approach.

Due to their high biocompatibility, intravitreal liposo-

mal formulations can sustain anti-VEGF drug release

for more than one month. In particular, multivesicu-

lar liposomes with an expanded aqueous core have

been developed to improve encapsulation efficiency

and to further extend duration of drug release  [147].

Finally, gene therapy using adeno-associated viral vec-

tors offers the potential for a long-term intraocular

expression of therapeutic anti-VEGF proteins. Despite

this advantage, safety-related concerns remain, such

as inflammatory responses and IOP reduction ob-

served in some studies, as well as challenges in pre-

cisely controlling transgene expression  [148]. It is

also noteworthy that corticosteroid therapy used as

an alternative in DME resistant to anti-VEGF agents,

can be delivered via intravitreal implants containing

dexamethasone or fluocinolone acetonide. However,

their clinical utility is constrained by the risk of ele-

vated IOP  [149].

Promising targeted therapy approaches. A key

priority in current research is identification of alter-

native pharmacological targets aimed at modulating

early pathogenic mechanisms in DR. Particular atten-

tion is given to compounds that inhibit the formation

of AGEs or block their interaction with RAGEs. One

such compound is epicatechin, which exhibits potent

anti-glycation activity and is capable of disrupting

formed cross-links both in  vitro and in  vivo, thereby

preventing endothelial cell apoptosis  [150]. In addi-

tion, AGE-specific DNA aptamers are being developed

to inhibit AGE–RAGE binding, reduce VEGF synthesis,

and exert retinoprotective effects  [151].

Other promising strategies are targeted antioxi-

dant and anti-inflammatory approaches, including the

use of nutraceuticals, such as resveratrol, quercetin,

and curcumin. However, their clinical application

is limited by poor bioavailability, which can be ad-

dressed through advanced drug delivery systems, in-

cluding liposomes, polymeric and solid lipid nanopar-

ticles, and nanoemulsions  [152,  153]. This category

also includes carotenoids, which are endogenous ret-

inal photoprotective and antioxidant compounds  [154,

155]. Recently, innovative strategies, such as mod-

ified nanoemulsion-based gels and specialized car-

rier proteins, have been actively explored for de-

livery of these water-insoluble molecules  [154-156].

The therapeutic efficacy of nutraceuticals is influenced

by factors such as early initiation of supplementation,

genetic predisposition, and individual patient charac-

teristics. Accordingly, they should be considered with-

in a personalized prevention framework rather than

as substitutes for established pharmacotherapy  [153].

Several DR-specific proteins are being studied as

pharmacological targets. These include HSPB4 (heat

shock protein family  B member  4), which suppresses

stress-induced expression of pro-inflammatory cyto-

kines in glial MCs, RAB20 (Ras-related protein Rab-20),

upregulation of which in hyperglycemia disrupts in-

tercellular communication of endotheliocytes and

MCs, KLKB1 (plasma kallikrein; regulator of vascular

permeability, inflammation, and edema) exhibiting

increased activity in the vitreous of patients at the

late stages of DR, and LRG1 (leucine-rich alpha-2-gly-

coprotein), which promotes pathological neovascu-

larization. Inhibitors of KLKB1 (NCT03466099) and

a monoclonal antibody against LRG1 (magacizumab)

currently undergo clinical evaluation  [157-159]. Final-

ly, due to their pronounced regulatory properties and

active participation in the pathogenesis of DR, some

microRNAs have emerged as promising therapeu-

tic tools. For example, modulation of miR-126 levels

helps restore vascular functions, inhibition of miR-21

reduces the activity of angiogenic signaling cascades

and alleviates retinal vascular damage. Upregulation

of miR-146a suppresses inflammation, reduces mi-

crovascular permeability, and improves retinal func-

tion  [79-81, 160].

Promising combined therapy approaches. Given

the multifactorial nature of DR, the most promising

therapeutic strategies might rely on a multi-target

approach that combines angiogenesis inhibition with

interventions addressing oxidative stress, inflamma-

tion, and metabolic dysregulation. A critical require-

ment for such strategies is the effective overcoming

SHEBARDINA et al.1330

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

of drug bioavailability limitations. One emerging ap-

proach involves mesenchymal stem cells (MSCs) and

their exosomes, which exhibit sustained immuno-

modulatory and anti-inflammatory effects. Exosomes

derived from adipose tissue MSCs can be engineered

to carry therapeutic cargoes such as miR-192. Intra-

vitreal administration of such modified exosomes re-

duces inflammation and pathological angiogenesis in

the retina  [161]. Similarly, bone marrow MSC-derived

exosomes have been shown to inhibit the Wnt/β–cat-

enin signaling pathway, thereby reducing oxidative

stress and suppressing expression of pro-inflamma-

tory mediators  [162].

Enhancing drug delivery efficiency is another

key objective in combined DR therapy development.

Nanoparticle-based systems capable of multi-ligand

targeting to retinal cell receptors, along with mucoad-

hesive properties and optimized surface charge, can

improve transport across biological barriers  [163].

This strategy enables modulation of core pathogen-

ic mechanisms, including impaired glucose transport

associated with reduced GLUT1 expression in retinal

capillaries and neurons  [164]. In this context, hyal-

uronic acid-based nanocarriers have been developed

for targeted delivery of GLUT1 to RPE cells via CD44

(cluster of differentiation  44) receptors. This ap-

proach not only normalizes glucose levels in the dia-

betic retina but also provides neuroprotection with a

favorable safety profile  [165]. Additionally, biomateri-

al-based scaffolds offer controlled, localized delivery

of therapeutic agents while providing intrinsic cyto-

protective effects  [166].

Overall, a shift toward combined pathogeneti-

cally oriented therapy via simultaneously targeting

oxidative stress (antioxidants, nutraceuticals), glyca-

tion (AGE inhibitors), inflammation (microRNAs, MSC

exosomes), dysfunction of specific molecular tar-

gets (KLKB1, LRG1, RAB20), and metabolic disorders

(targeted delivery of GLUT1) may alter the natural

course of DR, transforming it from progressive dis-

abling diseases to a manageable metabolic disorder.

Furthermore, the development of sustained-release

delivery systems for anti-VEGF agents, including

in  situ hydrogels, nanoparticles, liposomes, and gene

vectors, is expected to enhance therapeutic efficacy

while reducing the risk of surgical complications in

patients with PDR and DME.

CONCLUSION

Progress in anti-vasoproliferative therapies has

significantly enhanced the clinical capabilities of mod-

ern ophthalmology in the treatment of DR. However,

a fundamental challenge remains unresolved: the ab-

sence of comprehensive strategies for early disease

detection followed by individualized pathogenetic in-

tervention. Current approaches are largely directed

toward managing advanced disease stages. Identify-

ing the optimal time point for initiating targeted ther-

apy requires the development of novel tools of early

diagnostics. A promising strategy is a comprehensive

screening program for patients with diabetes, that

would integrate advanced retinal imaging techniques

with the assessment of biomarker panels in blood

and tear fluid. In parallel, artificial intelligence-based

algorithms may substantially improve the speed, ac-

curacy, and scalability of DR diagnostics and disease

monitoring. Recent advances in research have sig-

nificantly expanded our understanding of molecular

mechanisms underlying DR. In particular, the recog-

nition of neurodegeneration and oxidative stress as

early pathogenic factors has opened new avenues

for identifying pharmacological targets and optimiz-

ing drug delivery strategies. The integration of omics

data enables a system-level analysis of molecular al-

terations, facilitating identification of key regulatory

molecules involved in disease pathogenesis that may

serve as targets for innovative preventive and early

therapeutic interventions. Accordingly, the most ratio-

nal approach appears to be a multi-target therapeutic

strategy that combines inhibition of pathological an-

giogenesis with correction of metabolic dysregulation,

inflammation, and oxidative stress contributing to

neurovascular and neurodegenerative damage in DR.

Successful implementation of such integrated strategy

has a potential to substantially reduce the prevalence

of this socially significant disease, thereby improving

patients’ quality of life.

Abbreviations

AGEs advanced glycation end products

BRB blood–retinal barrier

CCL2 C-C motif chemokine ligand 2

DAG diacylglycerol

DM diabetes mellitus

DME diabetic macular edema

DR diabetic retinopathy

ECM extracellular matrix

FABP4 fatty acid binding protein 4

GDF15 growth differentiation factor 15

GLUT1 glucose transporter type 1

HIF1A hypoxia inducible factor 1 alpha

ICAM1 intercellular adhesion molecule 1

IGF1 insulin like growth factor 1

IOP intraocular pressure

MCs Müller cells

MSCs mesenchymal stem cells

NF-κB nuclear factor kappa light chain

enhancer of activated B cells

NPDR non-proliferative diabetic

retinopathy

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1331

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

PDR proliferative diabetic retinopathy

PKC protein kinase C

PPDR preproliferative diabetic

retinopathy

PRP panretinal photocoagulation

RAGE receptor for advanced glycation

end products

REN renin

ROS reactive oxygen species

RPE retinal pigment epithelium

VCAM vascular cell adhesion molecule 1

VEGF vascular endothelial growth factor

Supplementary information

The online version contains supplementary material

available at https://doi.org/10.1134/S000629792660105X.

Acknowledgments

Investigation of the molecular mechanisms of vision

and molecular bases of visual diseases are conduct-

ed under the State Assignment of the Lomonosov

Moscow State University.

Contributions

Conceptualization– N.G.S., A.M.M., and E.Y.Z.; drafting

of the original version – N.G.S., K.A.K., T.A.A., S.A.B.,

I.V.R., S.S.T., M.L.S., A.R.K., O.A.K., and E.Y.Z.; writing,

reviewing, and editing – N.G.S., E.S.G., A.A.Z., A.M.M.,

and E.Y.Z.; visualization and supplementary materi-

als – N.G.S. and K.A.K.; supervision – E.S.G., A.A.Z.,

A.M.M., and E.Y.Z.; project administration – N.G.S.

and E.Y.Z.; funding acquisition – E.Y.Z. All authors

have read and approved the manuscript.

Funding

This work was supported by the Russian Science

Foundation (project no. 24-15-00171).

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

REFERENCES

1. Yin, L., Zhang, D., Ren, Q., Su, X., and Sun, Z. (2020) Prevalence and risk factors of diabetic retinopathy in dia-

betic patients: a community based cross-sectional study, Medicine (Baltimore), 99, e19236, https://doi.org/10.1097/

MD.0000000000019236.

2. Sharma, A., Valle, M. L., Beveridge, C., Liu, Y., and Sharma, S. (2019) Unraveling the role of genetics in the

pathogenesis of diabetic retinopathy, Eye (Lond.), 33, 534-541, https://doi.org/10.1038/s41433-019-0337-y.

3. Teo, Z. L., Tham, Y.-C., Yu, M., Chee, M. L., Rim, T. H., Cheung, N., Bikbov, M. M., Wang, Y. X., Tang, Y.,

Lu, Y., Wong, I. Y., Ting, D. S. W., Tan, G. S. W., Jonas, J. B., Sabanayagam, C., Wong, T. Y., and Cheng, C.-Y.

(2021) Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and

meta-analysis, Ophthalmology, 128, 1580-1591, https://doi.org/10.1016/j.ophtha.2021.04.027.

4. Lipatov, D. V., Vikulova, O. K., Zheleznyakova, A. V., Isakov, M. A., Bessmertnaya, E. G., Tolkacheva, A. A.,

Chistyakov, T. A., Shestakova, M. V., and Dedov, I. I. (2018) Trends in the epidemiology of diabetic retinopa-

thy in Russian Federation according to the Federal Diabetes Register (2013-2016), Diabetes Mellit., 21, 230-240,

https://doi.org/10.14341/dm9797.

5. Early Treatment Diabetic Retinopathy Study Research Group (1991) Early photocoagulation for diabetic retinop-

athy. ETDRS report number 9. early treatment diabetic retinopathy study research group, Ophthalmology, 98,

766-785, https://doi.org/10.1016/S0161-6420(13)38011-7.

6. Li, H., Liu, X., Zhong, H., Fang, J., Li, X., Shi, R., and Yu, Q. (2023) Research progress on the pathogenesis of

diabetic retinopathy, BMC Ophthalmol., 23, 372, https://doi.org/10.1186/s12886-023-03118-6.

7. He, W., Tang, P., and Lv, H. (2025) Targeting oxidative stress in diabetic retinopathy: mechanisms, pathology,

and novel treatment approaches, Front. Immunol., 16, 1571576, https://doi.org/10.3389/fimmu.2025.1571576.

8. Zafar,S., Sachdeva,M., Frankfort, B.J., and Channa,R. (2019) Retinal neurodegeneration as an early manifestation

of diabetic eye disease and potential neuroprotective therapies, Curr. Diab. Rep., 19, 17, https://doi.org/10.1007/

s11892-019-1134-5.

9. Li, B., Yim, M. M., Jin, Y. X., Tao, B. K., Xie, J. S., Balas, M., Khan, H., Lam, W.-C., Yan, P., and Navajas, E. V.

(2025) Circulating cell-free DNA as an epigenetic biomarker for early diabetic retinopathy: a narrative review,

Diagnostics (Basel), 15, 1161, https://doi.org/10.3390/diagnostics15091161.

10. Mason, R. H., Minaker, S. A., Lahaie Luna, G., Bapat, P., Farahvash, A., Garg, A., Bhambra, N., and Muni, R. H.

(2025) Changes in aqueous and vitreous inflammatory cytokine levels in nonproliferative diabetic retinopathy:

systematic review and meta-analysis, Can. J. Ophthalmol., 60, e100-e116, https://doi.org/10.1016/j.jcjo.2024.05.031.

11. Gui, F., You, Z., Fu, S., Wu, H., and Zhang, Y. (2020) Endothelial dysfunction in diabetic retinopathy, Front. En-

docrinol. (Lausanne), 11, 591, https://doi.org/10.3389/fendo.2020.00591.

SHEBARDINA et al.1332

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

12. Li, C., Chen, X., Zhang, S., Liang, C., Deng, Q., Li, X., and Yan, H. (2024) Pericyte loss via glutaredoxin2 down-

regulation aggravates diabetes-induced microvascular dysfunction, Exp. Eye Res., 247, 110025, https://doi.org/

10.1016/j.exer.2024.110025.

13. Pretorius, L., Thomson, G. J. A., Adams, R. C. M., Nell, T. A., Laubscher, W. A., and Pretorius, E. (2018) Platelet

activity and hypercoagulation in type 2 diabetes, Cardiovasc. Diabetol., 17, 141, https://doi.org/10.1186/s12933-

018-0783-z.

14. Sobczak, A. I. S., and Stewart, A. J. (2019) Coagulatory defects in type-1 and type-2 diabetes, Int. J. Mol. Sci.,

20, 6345, https://doi.org/10.3390/ijms20246345.

15. Palenski, T. L., Sorenson, C. M., and Sheibani, N. (2013) Inflammatory cytokine-specific alterations in retinal

endothelial cell function, Microvasc. Res., 89, 57-69, https://doi.org/10.1016/j.mvr.2013.06.007.

16. Mohamed, R., Sharma, I., Ibrahim, A. S., Saleh, H., Elsherbiny, N. M., Fulzele, S., Elmasry, K., Smith, S. B.,

Al-Shabrawey, M., and Tawfik, A. (2017) Hyperhomocysteinemia alters retinal endothelial cells barrier function

and angiogenic potential via activation of oxidative stress, Sci. Rep., 7, 11952, https://doi.org/10.1038/s41598-

017-09731-y.

17. Biletskaya, V. A., Lipatov, D. V., Sayapina, I. Y., Frolov, M. A., and Surguch, V. K. (2022) Markers of proliferative

diabetic retinopathy, Ophthalmol. Russ., 19, 557-564, https://doi.org/10.18008/1816-5095-2022-3-557-564.

18. Lipatov, D. V., Kuz’min, A. G., Tolkacheva, A. A., and Chistyakov, T. A. (2012) Features of proliferative process

in patients with diabetic retinopathy, Diabetes Mellit., 15, 99-102, https://doi.org/10.14341/2072-0351-5526.

19. Wong, T. Y., Sun, J., Kawasaki, R., Ruamviboonsuk, P., Gupta, N., Lansingh, V. C., Maia, M., Mathenge, W.,

Moreker, S., Muqit, M. M. K., Resnikoff, S., Verdaguer, J., Zhao, P., Ferris, F., Aiello, L. P., and Taylor, H. R.

(2018) Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screen-

ing, follow-up, referral, and treatment based on resource settings, Ophthalmology, 125, 1608-1622, https://

doi.org/10.1016/j.ophtha.2018.04.007.

20. Callan, A., Heckman, J., Tah, G., Lopez, S., Valdez, L., and Tsin, A. (2025) VEGF in diabetic retinopathy and

age-related macular degeneration, Int. J. Mol. Sci., 26, 4992, https://doi.org/10.3390/ijms26114992.

21. Reddy, S. K., Devi, V., Seetharaman, A. T. M., Shailaja, S., Bhat, K. M. R., Gangaraju, R., and Upadhya, D. (2024)

Cell and molecular targeted therapies for diabetic retinopathy, Front. Endocrinol. (Lausanne), 15, 1416668, https://

doi.org/10.3389/fendo.2024.1416668.

22. Walton, M., Bojke, L., Simmonds, M., Walker, R., Llewellyn, A., Fulbright, H., Dias, S., Stewart, L. A., Rush, T.,

Steel, D. H., Lawrenson, J. G., Peto, T., and Hodgson, R. (2024) Anti-vascular endothelial growth factor drugs

compared with panretinal photocoagulation for the treatment of proliferative diabetic retinopathy: a cost-effec-

tiveness analysis, Value Health, 27, 907-917, https://doi.org/10.1016/j.jval.2024.03.007.

23. Regillo, C. D., Callanan, D. G., Do, D. V., Fine, H. F., Holekamp, N. M., Kuppermann, B. D., Singer, M. A., and

Singh, R. P. (2017) Use of corticosteroids in the treatment of patients with diabetic macular edema who have

a suboptimal response to anti-VEGF: recommendations of an expert panel, Ophthalmic Surg. Lasers Imaging

Retina, 48, 291-301, https://doi.org/10.3928/23258160-20170329-03.

24. Fuseini, M.-S., Gbedemah, Z. E., Ahmed, A., Adenekan, A. O., Bourkiza, R., Mowatt, L., Osuji, N., Mwangi, N.,

Scott, A. W., Mensah, E., Faal, H. B., Amoaku, W. M. K., Sivaprasad, S., Hanson, J. E., Itua, I. O. G., and

Amissah-Arthur, K. N. (2025) Global publication trends on sickle cell and diabetic retinopathy over eight de-

cades: a highlight on information disparity: SCRnet consortium paper 1, Eye Open, 1, 4, https://doi.org/10.1038/

s44440-025-00005-5.

25. Zhang, Q., Zhang, P., Chen, N., Zhu, Z., Li, W., and Wang, Q. (2024) Trends and hotspots in the field of di-

abetic retinopathy imaging research from 2000-2023, Front. Med. (Lausanne), 11, 1481088, https://doi.org/

10.3389/fmed.2024.1481088.

26. Srivastava, R., Mishra, D., Singh, D., Reddy, M. Y., Parihar, S., and Palandurkar, K. (2026) The AGE-RAGE-oxi-

dative stress axis: a paradigm shift in understanding diabetic retinopathy, Indian J. Ophthalmol., 74, 190-195,

https://doi.org/10.4103/IJO.IJO_1643_25.

27. Ansari, P., Tabasumma, N., Snigdha, N. N., Siam, N. H., Panduru, R. V. N. R. S., Azam, S., Hannan, J. M. A., and

Abdel-Wahab, Y. H. A. (2022) Diabetic retinopathy: an overview on mechanisms, pathophysiology and pharma-

cotherapy, Diabetology (Basel), 3, 159-175, https://doi.org/10.3390/diabetology3010011.

28. Zhou, M., Zhang, Y., Shi, L., Li, L., Zhang, D., Gong, Z., and Wu, Q. (2024) Activation and modulation of the

AGEs-RAGE axis: implications for inflammatory pathologies and therapeutic interventions – a review, Pharmacol.

Res., 206, 107282, https://doi.org/10.1016/j.phrs.2024.107282.

29. Nolfi-Donegan, D., Braganza, A., and Shiva, S. (2020) Mitochondrial electron transport chain: oxidative phos-

phorylation, oxidant production, and methods of measurement, Redox Biol., 37, 101674, https://doi.org/

10.1016/j.redox.2020.101674.

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1333

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

30. Kang, Q., and Yang, C. (2020) Oxidative stress and diabetic retinopathy: molecular mechanisms, pathogenetic

role and therapeutic implications, Redox Biol., 37, 101799, https://doi.org/10.1016/j.redox.2020.101799.

31. Lorenzi, M. (2007) The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient,

Exp. Diabetes Res., 2007, 61038, https://doi.org/10.1155/2007/61038.

32. Chistiakov, D. A. (2011) Diabetic retinopathy: pathogenic mechanisms and current treatments, Diabetes Metab.

Syndr., 5, 165-172, https://doi.org/10.1016/j.dsx.2012.02.025.

33. Kowluru, R. A., and Chan, P.-S. (2007) Oxidative stress and diabetic retinopathy, Exp. Diabetes Res., 2007, 43603,

https://doi.org/10.1155/2007/43603.

34. Oshitari, T. (2023) Neurovascular cell death and therapeutic strategies for diabetic retinopathy, Int. J. Mol. Sci.,

24, 12919, https://doi.org/10.3390/ijms241612919.

35. Nicholls, D. G. (2004) Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal

cultures, Curr. Mol. Med., 4, 149-177, https://doi.org/10.2174/1566524043479239.

36. Wu, W.-L., Gong, X.-X., Qin, Z.-H., and Wang, Y. (2025) Molecular mechanisms of excitotoxicity and their rel-

evance to the pathogenesis of neurodegenerative diseases-an update, Acta Pharmacol. Sin., 46, 3129-3142,

https://doi.org/10.1038/s41401-025-01576-w.

37. Lu, Z., Fan, B., Li, Y., and Zhang, Y. (2023) RAGE plays key role in diabetic retinopathy: a review, Biomed. Eng.

Online, 22, 128, https://doi.org/10.1186/s12938-023-01194-9.

38. Ding, X., Sun, Z., Guo, Y., Tang, W., Shu, Q., and Xu, G. (2023) Inhibition of NF-κB ameliorates aberrant retinal

glia activation and inflammatory responses in streptozotocin-induced diabetic rats, Ann. Transl. Med., 11, 197,

https://doi.org/10.21037/atm-22-2204.

39. Tang, J., and Kern, T. S. (2011) Inflammation in diabetic retinopathy, Prog. Retin. Eye Res., 30, 343-358,

https://doi.org/10.1016/j.preteyeres.2011.05.002.

40. Rübsam, A., Parikh, S., and Fort, P. E. (2018) Role of inflammation in diabetic retinopathy, Int. J. Mol. Sci., 19,

942, https://doi.org/10.3390/ijms19040942.

41. Noort, A. R., van Zoest, K. P. M., Weijers, E. M., Koolwijk, P., Maracle, C. X., Novack, D. V., Siemerink, M. J.,

Schlingemann, R. O., Tak, P. P., and Tas, S. W. (2014) NF-κB-inducing kinase is a key regulator of inflamma-

tion-induced and tumour-associated angiogenesis, J. Pathol., 234, 375-385, https://doi.org/10.1002/path.4403.

42. Yumnamcha, T., Guerra, M., Singh, L. P., and Ibrahim, A. S. (2020) Metabolic dysregulation and neurovascular

dysfunction in diabetic retinopathy, Antioxidants (Basel), 9, 1244, https://doi.org/10.3390/antiox9121244.

43. Fadini, G. P., Cappellari, R., Mazzucato, M., Agostini, C., Vigili de Kreutzenberg, S., and Avogaro, A. (2013)

Monocyte-macrophage polarization balance in pre-diabetic individuals, Acta Diabetol., 50, 977-982, https://

doi.org/10.1007/s00592-013-0517-3.

44. Zhang, X., Zhang, F., and Xu, X. (2024) Single-cell RNA sequencing in exploring the pathogenesis of diabetic

retinopathy, Clin. Transl. Med., 14, e1751, https://doi.org/10.1002/ctm2.1751.

45. Chen, T., Zhu, W., Wang, C., Dong, X., Yu, F., Su, Y., Huang, J., Huo, L., and Wan, P. (2022) ALKBH5-mediated

A modification of A20 regulates microglia polarization in diabetic retinopathy, Front. Immunol., 13, 813979,

https://doi.org/10.3389/fimmu.2022.813979.

46. Singh, V., Kaur, R., Kumari, P., Pasricha, C., and Singh, R. (2023) ICAM-1 and VCAM-1: gatekeepers in var-

ious inflammatory and cardiovascular disorders, Clin. Chim. Acta, 548, 117487, https://doi.org/10.1016/

j.cca.2023.117487.

47. Ishida, S., Usui, T., Yamashiro, K., Kaji, Y., Ahmed, E., Carrasquillo, K. G., Amano, S., Hida, T., Oguchi, Y., and

Adamis, A. P. (2003) VEGF164 is proinflammatory in the diabetic retina, Invest. Ophthalmol. Vis. Sci., 44,

2155-2162, https://doi.org/10.1167/iovs.02-0807.

48. Miyamoto, K., Khosrof, S., Bursell, S. E., Rohan, R., Murata, T., Clermont, A. C., Aiello, L. P., Ogura, Y., and

Adamis, A. P. (1999) Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic reti-

nopathy via intercellular adhesion molecule-1 inhibition, Proc. Natl. Acad. Sci. USA, 96, 10836-10841, https://

doi.org/10.1073/pnas.96.19.10836.

49. Park, S. W., Yun, J.-H., Kim, J. H., Kim, K.-W., Cho, C.-H., and Kim, J. H. (2014) Angiopoietin 2 induces peri-

cyte apoptosis via α3β1 integrin signaling in diabetic retinopathy, Diabetes, 63, 3057-3068, https://doi.org/

10.2337/db13-1942.

50. Whitehead, M., Osborne, A., Widdowson, P. S., Yu-Wai-Man, P., and Martin, K. R. (2019) Angiopoietins in di-

abetic retinopathy: current understanding and therapeutic potential, J. Diabetes Res., 2019, 5140521, https://

doi.org/10.1155/2019/5140521.

51. Barber, A. J., Lieth, E., Khin, S. A., Antonetti, D. A., Buchanan, A. G., and Gardner, T. W. (1998) Neural apoptosis

in the retina during experimental and human diabetes. Early onset and effect of insulin, J. Clin. Invest., 102,

783-791, https://doi.org/10.1172/JCI2425.

SHEBARDINA et al.1334

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

52. Abu El-Asrar, A. M., Dralands, L., Missotten, L., and Geboes, K. (2007) Expression of antiapoptotic and proapop-

totic molecules in diabetic retinas, Eye (Lond.), 21, 238-245, https://doi.org/10.1038/sj.eye.6702225.

53. Huber, K. L., Himmel, D., Steiner, I., Jeremic, N., Widmann-Sedlnitzky, P., Stino, H., Kunze, L., Reiter, G. S.,

Schmidt-Erfurth, U., and Pollreisz, A. (2026) Evaluation of photoreceptor integrity in diabetic retinopa-

thy using high-resolution optical coherence tomography, Eye (Lond.), https://doi.org/10.1038/s41433-026-

04353-z.

54. Ren, J., Zhang, S., Pan, Y., Jin, M., Li, J., Luo, Y., Sun, X., and Li, G. (2022) Diabetic retinopathy: involved cells,

biomarkers, and treatments, Front. Pharmacol., 13, 953691, https://doi.org/10.3389/fphar.2022.953691.

55. Zhou, J., and Chen, B. (2023) Retinal cell damage in diabetic retinopathy, Cells, 12, 1342, https://doi.org/10.3390/

cells12091342.

56. Llorián-Salvador, M., Cabeza-Fernández, S., Gomez-Sanchez, J. A., and de la Fuente, A. G. (2024) Glial

cell alterations in diabetes-induced neurodegeneration, Cell. Mol. Life Sci., 81, 47, https://doi.org/10.1007/

s00018-023-05024-y.

57. Bogdanov, P., Corraliza, L., Villena, J. A., Carvalho, A. R., Garcia-Arumí, J., Ramos, D., Ruberte, J., Simó, R., and

Hernández, C. (2014) The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration,

PLoS One, 9, e97302, https://doi.org/10.1371/journal.pone.0097302.

58. Wu, D., Kanda, A., Liu, Y., Noda, K., Murata, M., and Ishida, S. (2020) Involvement of Müller glial autoinduction

of TGF-β in diabetic fibrovascular proliferation via glial-mesenchymal transition, Invest. Ophthalmol. Vis. Sci.,

61, 29, https://doi.org/10.1167/iovs.61.14.29.

59. Pitale, P. M., Saltykova, I. V., Adu-Agyeiwaah, Y., Li Calzi, S., Satoh, T., Akira, S., Gorbatyuk, O., Boulton, M. E.,

Pardue, M. T., Garvey, W. T., Athar, M., Grant, M. B., and Gorbatyuk, M. S. (2021) Tribbles homolog 3 medi-

ates the development and progression of diabetic retinopathy, Diabetes, 70, 1738-1753, https://doi.org/10.2337/

db20-1268.

60. Yun, J.-H., Park, S. W., Kim, J. H., Park, Y.-J., Cho, C.-H., and Kim, J. H. (2016) Angiopoietin 2 induces as-

trocyte apoptosis via αvβ5-integrin signaling in diabetic retinopathy, Cell Death Dis., 7, e2101, https://doi.org/

10.1038/cddis.2015.347.

61. Pan, D., Xu, L., and Guo, M. (2022) The role of protein kinase C in diabetic microvascular complications, Front.

Endocrinol. (Lausanne), 13, 973058, https://doi.org/10.3389/fendo.2022.973058.

62. Ferrara, N., Gerber, H.-P., and LeCouter, J. (2003) The biology of VEGF and its receptors, Nat. Med., 9, 669-676,

https://doi.org/10.1038/nm0603-669.

63. Park, J. E., Keller, G. A., and Ferrara, N. (1993) The vascular endothelial growth factor (VEGF) isoforms: differ-

ential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF,

Mol. Biol. Cell, 4, 1317-1326, https://doi.org/10.1091/mbc.4.12.1317.

64. Lee, C., Kim, M.-J., Kumar, A., Lee, H.-W., Yang, Y., and Kim, Y. (2025) Vascular endothelial growth factor signaling

in health and disease: from molecular mechanisms to therapeutic perspectives, Signal. Transduct. Target Ther.,

10, 170, https://doi.org/10.1038/s41392-025-02249-0.

65. Zhang, M., Tombran-Tink, J., Yang, S., Zhang, X., Li, X., and Barnstable, C. J. (2021) PEDF is an endogenous

inhibitor of VEGF-R2 angiogenesis signaling in endothelial cells, Exp. Eye Res., 213, 108828, https://doi.org/

10.1016/j.exer.2021.108828.

66. Haurigot, V., Villacampa, P., Ribera, A., Llombart, C., Bosch, A., Nacher, V., Ramos, D., Ayuso, E., Segovia, J. C.,

Bueren, J. A., Ruberte, J., and Bosch, F. (2009) Increased intraocular insulin-like growth factor-I triggers blood-

retinal barrier breakdown, J. Biol. Chem., 284, 22961-22969, https://doi.org/10.1074/jbc.M109.014787.

67. Malepati, A., and Grant, M. B. (2025) The role and diagnostic potential of insulin-like growth factor 1

in diabetic retinopathy and diabetic macular edema, Int. J. Mol. Sci., 26, 3961, https://doi.org/10.3390/

ijms26093961.

68. Seigel, G. M., Lupien, S. B., Campbell, L. M., and Ishii, D. N. (2006) Systemic IGF-I treatment inhibits cell death

in diabetic rat retina, J. Diabetes Complications, 20, 196-204, https://doi.org/10.1016/j.jdiacomp.2005.06.007.

69. Rajala, A., Teel, K., Bhat, M. A., Batushansky, A., Griffin, T. M., Purcell, L., and Rajala, R. V. S. (2022) Insu-

lin-like growth factor 1 receptor mediates photoreceptor neuroprotection, Cell Death Dis., 13, 613, https://doi.org/

10.1038/s41419-022-05074-3.

70. Rajala, R. V. S., and Rajala, A. (2024) From insight to eyesight: unveiling the secrets of the insulin-like growth

factor axis in retinal health, Aging Dis., 15, 1994-2002, https://doi.org/10.14336/AD.2024.0128.

71. Huber, A. L., Angermann, R., Nowosielski, Y., Seifarth, C., Kralinger, M. T., and Zehetner, C. (2021) Effects of

intravitreal aflibercept on the systemic insulin-like growth factor-I and vascular endothelial growth factor-A

in patients with diabetic retinopathy and age-related macular degeneration, J. Ophthalmol., 2021, 7058505,

https://doi.org/10.1155/2021/7058505.

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1335

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

72. Raman, P., Singal, A. K., and Behl, A. (2019) Effect of insulin-like growth factor-1 on diabetic retinopathy

in pubertal age patients with type 1 diabetes, Asia Pac. J. Ophthalmol. (Phila.), 8, 319-323, https://doi.org/

10.1097/APO.0000000000000250.

73. Shajahan, S., Nagarajan, H., Ranganathan, S., Karunakaran, C. M., and Subramaniam Rajesh, B. (2025) Novel

FBXW7 hypermethylation in a carboxymethyl lysine- driven retinal co-culture model: an epigenetic bio-

marker with translational potential for diabetic retinopathy, Comput. Biol. Med., 199, 111315, https://doi.org/

10.1016/j.compbiomed.2025.111315.

74. Cai, C., Gu, C., Meng, C., Wang, Y., Wei, Q., He, S., Lai, D., Wang, X., Wang, T., and Qiu, Q. (2025) DNA

hypermethylation of PLTP mediated by DNMT3B aggravates vascular dysfunction in diabetic retinop-

athy via the AKT/GSK3β signaling pathway, Clin. Epigenet., 17, 82, https://doi.org/10.1186/s13148-025-

01874-4.

75. Lu, Y., Zhang, Y., Yao, J., Bai, W., and Li, K. (2025) Histone modifications: potential therapeutic targets

for diabetic retinopathy, Biomolecules, 15, 575, https://doi.org/10.3390/biom15040575.

76. Wang, J., Yin, Z., Yang, J., Sun, S., Tang, X., Zhang, S., Wang, Y.-P., and Wang, H. (2025) BCAT1 activation re-

programs branched-chain amino acid metabolism and epigenetically promotes inflammation in diabetic

retinopathy, Invest. Ophthalmol. Vis. Sci., 66, 59, https://doi.org/10.1167/iovs.66.6.59.

77. Guo, S., Ye, M., Zhu, W., and Liu, C. (2025) From fuel to epigenetic signal: Lactate-lactylation axis orchestrates

diabetic complications, Pharmacol. Res., 222, 108052, https://doi.org/10.1016/j.phrs.2025.108052.

78. Lampsas,S., Agapitou,C., Chatzirallis,A., Papavasileiou,G., Poulakis,D., Pegka,S., Theodossiadis,P., Lambadiari,V.,

and Chatziralli, I. (2025) MicroRNA (miRNA) in the pathogenesis of diabetic retinopathy: a narrative review,

Genes (Basel), 16, 1060, https://doi.org/10.3390/genes16091060.

79. Wu, K., Yang, Y., Zhong, Y., Ammar, H. M., Zhang, P., Guo, R., Liu, H., Cheng, C., Koroscil, T. M., Chen, Y.,

Liu, S., and Bihl, J. C. (2016) The effects of microvesicles on endothelial progenitor cells are compromised in

type 2 diabetic patients via downregulation of the miR-126/VEGFR2 pathway, Am. J. Physiol. Endocrinol. Metab.,

310, E828-E837, https://doi.org/10.1152/ajpendo.00056.2016.

80. Taganov, K. D., Boldin, M. P., Chang, K.-J., and Baltimore, D. (2006) NF-kappaB-dependent induction of microRNA

miR-146, an inhibitor targeted to signaling proteins of innate immune responses, Proc. Natl. Acad. Sci. USA,

103, 12481-12486, https://doi.org/10.1073/pnas.0605298103.

81. Zhuang, P., Muraleedharan, C. K., and Xu, S. (2017) Intraocular delivery of miR-146 inhibits diabetes-induced

retinal functional defects in diabetic rat model, Invest. Ophthalmol. Vis. Sci., 58, 1646-1655, https://doi.org/

10.1167/iovs.16-21223.

82. Qin, B., Liu, J., Liu, S., Li, B., and Ren, J. (2016) MiR-20b targets AKT3 and modulates vascular endothelial

growth factor-mediated changes in diabetic retinopathy, Acta Biochim. Biophys. Sin. (Shanghai), 48, 732-740,

https://doi.org/10.1093/abbs/gmw065.

83. Gong, R., Han, R., Zhuang, X., Tang, W., Xu, G., Zhang, L., Wu, J., and Ma, J. (2022) MiR-375 mitigates ret-

inal angiogenesis by depressing the JAK2/STAT3 pathway, Aging (Albany NY), 14, 6594-6604, https://doi.org/

10.18632/aging.204232.

84. Ménard, C., Wilson, A. M., Dejda, A., Miloudi, K., Binet, F., Crespo-Garcia, S., Parinot, C., Pilon, F., Juneau, R.,

Andriessen, E. M., Mawambo, G., SanGiovanni, J. P., de Guire, V., and Sapieha, P. (2020) miR-106b suppresses

pathological retinal angiogenesis, Aging (Albany  NY), 12, 24836-24852, https://doi.org/10.18632/aging.202404.

85. Guo, N., Nulahou, A., Bu, Q., Liu, M., Wang, Y., Zhao, Y., Yang, L., and Gao, Y. (2020) MiR-542-5p regulates

the progression of diabetic retinopathy by targeting CARM1, Acta Biochim. Pol., 67, 373-378, https://doi.org/

10.18388/abp.2020_5228.

86. Shao, Y., Dong, L.-J., Takahashi, Y., Chen, J., Liu, X., Chen, Q., Ma, J., and Li, X. (2019) miRNA-451a regulates

RPE function through promoting mitochondrial function in proliferative diabetic retinopathy, Am. J. Physiol.

Endocrinol. Metab., 316, E443-E452, https://doi.org/10.1152/ajpendo.00360.2018.

87. Wang, M., Zheng, H., Zhou, X., Zhang, J., and Shao, G. (2020) miR-122 promotes diabetic retinopathy through

targeting TIMP3, Anim. Cells Syst. (Seoul), 24, 275-281, https://doi.org/10.1080/19768354.2020.1816580.

88. Wang, J., Yao, Y., Wang, K., Li, J., Chu, T., and Shen, H. (2020) MicroRNA-148a-3p alleviates high glucose-

induced diabetic retinopathy by targeting TGFB2 and FGF2, Acta Diabetol., 57, 1435-1443, https://doi.org/

10.1007/s00592-020-01569-7.

89. Zeng, F., Luo, G., Lu, Y., Zhang, Z., Zhou, Y., Chen, Y., and Zhou, Z. (2020) Long non-coding RNA VIM Antisense

RNA 1 (VIM-AS1) sponges microRNA-29 to participate in diabetic retinopathy, Acta Diabetol., 57, 1111-1116,

https://doi.org/10.1007/s00592-020-01536-2.

90. Cho, H., and Sobrin, L. (2014) Genetics of diabetic retinopathy, Curr. Diab. Rep., 14, 515, https://doi.org/

10.1007/s11892-014-0515-z.

SHEBARDINA et al.1336

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

91. Sienkiewicz-Szłapka, E., Fiedorowicz, E., Król-Grzymała, A., Kordulewska, N., Rozmus, D., Cieślińska, A., and

Grzybowski, A. (2023) The role of genetic polymorphisms in diabetic retinopathy: narrative review, Int. J. Mol.

Sci., 24, 15865, https://doi.org/10.3390/ijms242115865.

92. Abhary, S., Burdon, K. P., Laurie, K. J., Thorpe, S., Landers, J., Goold, L., Lake, S., Petrovsky, N., and Craig, J. E.

(2010) Aldose reductase gene polymorphisms and diabetic retinopathy susceptibility, Diabetes Care, 33,

1834-1836, https://doi.org/10.2337/dc09-1893.

93. Kaur, N., and Vanita, V. (2016) Association of aldose reductase gene (AKR1B1) polymorphism with diabetic

retinopathy, Diabetes Res. Clin. Pract., 121, 41-48, https://doi.org/10.1016/j.diabres.2016.08.019.

94. Luo, S., Shi, C., Wang, F., and Wu, Z. (2016) Association between the angiotensin-converting enzyme (ACE) ge-

netic polymorphism and diabetic retinopathy – A meta-analysis comprising 10,168 subjects, Int. J. Environ. Res.

Public Health, 13, 1142, https://doi.org/10.3390/ijerph13111142.

95. Niu, W., and Qi, Y. (2012) An updated meta-analysis of methylenetetrahydrofolate reductase gene 677C/T

polymorphism with diabetic nephropathy and diabetic retinopathy, Diabetes Res. Clin. Pract., 95, 110-118,

https://doi.org/10.1016/j.diabres.2011.10.009.

96. Garcia-Hernandez, S. C., Porchia, L. M., López-Bayghen, E., and Gonzalez-Mejia, M. E. (2019) The A1298C

methylenetetrahydrofolate reductase polymorphism augments the risk of developing of diabetic retinopathy:

a meta-analysis, Meta Gene, 20, 100560, https://doi.org/10.1016/j.mgene.2019.100560.

97. Lu, Y., Ge, Y., Shi, Y., Yin, J., and Huang, Z. (2013) Two polymorphisms (rs699947, rs2010963) in the VEGFA

gene and diabetic retinopathy: an updated meta-analysis, BMC Ophthalmol., 13, 56, https://doi.org/10.1186/

1471-2415-13-56.

98. Xie, X.-J., Yang, Y.-M., Jiang, J.-K., and Lu, Y.-Q. (2017) Association between the vascular endothelial growth

factor single nucleotide polymorphisms and diabetic retinopathy risk: a meta-analysis, J. Diabetes, 9, 738-753,

https://doi.org/10.1111/1753-0407.12480.

99. Chistyakov, D. V., Belousov, A. S., Shevelyova, M. P., Iomdina, E. N., Baksheeva, V. E., Shebardina, N. G.,

Moysenovich, A. M., Bulgakov, T. K., Petrov, S. Yu., Shishkin, M. L., Tulush, S. S., Tiulina, V. V., Pogodina, E. I.,

Gancharova, O. S., Filippova, O. M., Baldin, A. V., Goriainov, S. V., Nikolskaya, A. I., Zalevsky, A. O., et al. (2025)

A role of pigment epithelium-derived factor in zinc-mediated mechanism of neurodegeneration in glaucoma,

Commun. Biol., 8, 965, https://doi.org/10.1038/s42003-025-08370-8.

100. Shebardina, N. G., Petrov, S. Yu., Iomdina, E. N., Novikova, N. N., Goriainov, S. V., Ivlev, V. A., Zhuravleva, A. N.,

Tulush, S. S., Shishkin, M. L., Gorbatenko, V. O., Starostina, A. V., Filippova, O. M., Oganesyan, O. G.,

Korchuganova, E. A., Ilyukhin, O. E., Vasil’ev, V. G., Sergeeva, M. G., Chistyakov, D. V., and Zernii, E. Yu. (2026)

Molecular portraits of aqueous humor in primary and pseudoexfoliative open-angle glaucoma, J. Proteome

Res., 25, 1700-1713, https://doi.org/10.1021/acs.jproteome.5c00982.

101. Azbukina, N. V., Chistyakov, D. V., Goriainov, S. V., Kotelin, V. I., Fedoseeva, E. V., Petrov, S. Yu.,

Sergeeva, M. G., Iomdina, E. N., and Zernii, E. Yu. (2021) Targeted lipidomic analysis of aqueous humor re-

veals signaling lipid-mediated pathways in primary open-angle glaucoma, Biology (Basel), 10, 658, https://doi.org/

10.3390/biology10070658.

102. Dascalu, A. M., Anghelache, A., Stana, D., Costea, A. C., Nicolae, V. A., Tanasescu, D., Costea, D., Tribus, L.,

Zgura, A., Serban, D., Duta, L., Tudosie, M., Balasescu, S., Tanasescu, C., and Tudosie, M. (2022) Serum levels

of copper and zinc in diabetic retinopathy: Potential new therapeutic targets (review), Exp. Ther. Med.,

23, 324, https://doi.org/10.3892/etm.2022.11253.

103. Miao, X., Sun, W., Miao, L., Fu, Y., Wang, Y., Su, G., and Liu, Q. (2013) Zinc and diabetic retinopathy, J. Diabetes

Res., 2013, 425854, https://doi.org/10.1155/2013/425854.

104. Ali, H., Al-Fartusie, F. S., and Abduljabbar, R. A. (2025) Assessment of trace element imbalances in diabetes

mellitus patients with and without diabetic retinopathy: a case-control study in Iraq, Biometals, 38, 1917-1929,

https://doi.org/10.1007/s10534-025-00738-x.

105. Liew, G., Lei, Z., Tan, G., Joachim, N., Ho, I.-V., Wong, T. Y., Mitchell, P., Gopinath, B., and Crossett, B. (2017)

Metabolomics of diabetic retinopathy, Curr. Diab. Rep., 17, 102, https://doi.org/10.1007/s11892-017-0939-3.

106. Tomita, Y., Cagnone, G., Fu, Z., Cakir, B., Kotoda, Y., Asakage, M., Wakabayashi, Y., Hellström, A., Joyal, J.-S.,

Talukdar, S., Smith, L. E. H., and Usui, Y. (2021) Vitreous metabolomics profiling of proliferative diabetic

retinopathy, Diabetologia, 64, 70-82, https://doi.org/10.1007/s00125-020-05309-y.

107. Zhu, D.-D., Wang, Y.-Z., Zou, C., She, X.-P., and Zheng, Z. (2018) The role of uric acid in the pathogenesis of

diabetic retinopathy based on Notch pathway, Biochem. Biophys. Res. Commun., 503, 921-929, https://doi.org/

10.1016/j.bbrc.2018.06.097.

108. Yoon, M.-S. (2016) The emerging role of branched-chain amino acids in insulin resistance and metabolism,

Nutrients, 8, 405, https://doi.org/10.3390/nu8070405.

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1337

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

109. Wei, J., Jiang, H., Gao, H., and Wang, G. (2016) Blocking mammalian target of rapamycin (mTOR) attenuates

HIF-1α pathways engaged-vascular endothelial growth factor (VEGF) in diabetic retinopathy, Cell Physiol. Bio-

chem., 40, 1570-1577, https://doi.org/10.1159/000453207.

110. Ding, C., Wang, N., Wang, Z., Yue, W., Li, B., Zeng, J., Yoshida, S., Yang, Y., and Zhou, Y. (2022) Integrated analy-

sis of metabolomics and lipidomics in plasma of T2DM patients with diabetic retinopathy, Pharmaceutics, 14,

2751, https://doi.org/10.3390/pharmaceutics14122751.

111. Wang, J., Shao, Z., Li, W., Zhao, Y., Li, S., Ma, C., and Li, J. (2025) Lipidomic analysis of vitreous humor de-

rived from patients with proliferative diabetic retinopathy, BMC Ophthalmol., 25, 545, https://doi.org/10.1186/

s12886-025-04347-7.

112. Wilmott, L. A., Grambergs, R. C., Allegood, J. C., Lyons, T. J., and Mandal, N. (2019) Analysis of sphingolipid

composition in human vitreous from control and diabetic individuals, J. Diabetes Complications, 33, 195-201,

https://doi.org/10.1016/j.jdiacomp.2018.12.005.

113. Shiba, T., Inoguchi, T., Sportsman, J. R., Heath, W. F., Bursell, S., and King, G. L. (1993) Correlation of diacyl-

glycerol level and protein kinase C activity in rat retina to retinal circulation, Am. J. Physiol., 265, E783-E793,

https://doi.org/10.1152/ajpendo.1993.265.5.E783.

114. Ferrucci, L., Cherubini, A., Bandinelli, S., Bartali, B., Corsi, A., Lauretani, F., Martin, A., Andres-Lacueva, C.,

Senin, U., and Guralnik, J. M. (2006) Relationship of plasma polyunsaturated fatty acids to circulating inflam-

matory markers, J. Clin. Endocrinol. Metab., 91, 439-446, https://doi.org/10.1210/jc.2005-1303.

115. Huang, F., Subbaiah, P. V., Holian, O., Zhang, J., Johnson, A., Gertzberg, N., and Lum, H. (2005) Lysophosphati-

dylcholine increases endothelial permeability: role of PKCalpha and RhoA cross talk, Am. J. Physiol. Lung Cell.

Mol. Physiol., 289, L176-L185, https://doi.org/10.1152/ajplung.00003.2005.

116. Canning, P., Kenny, B.-A., Prise, V., Glenn, J., Sarker, M. H., Hudson, N., Brandt, M., Lopez, F. J., Gale, D.,

Luthert, P. J., Adamson,P., Turowski,P., and Stitt, A. W. (2016) Lipoprotein-associated phospholipase A2 (Lp-PLA2)

as a therapeutic target to prevent retinal vasopermeability during diabetes, Proc. Natl. Acad. Sci. USA, 113,

7213-7218, https://doi.org/10.1073/pnas.1514213113.

117. Sharma, S., Purohit, S., Sharma, A., Hopkins, D., Steed, L., Bode, B., Anderson, S. W., Caldwell, R., and

She, J.-X. (2015) Elevated serum levels of soluble TNF receptors and adhesion molecules are associated

with diabetic retinopathy in patients with type-1 Diabetes, Mediators Inflamm., 2015, 279393, https://doi.org/

10.1155/2015/279393.

118. Lu, C.-H., Lin, S.-T., Chou, H.-C., Lee, Y.-R., and Chan, H.-L. (2013) Proteomic analysis of retinopathy-related

plasma biomarkers in diabetic patients, Arch. Biochem. Biophys., 529, 146-156, https://doi.org/10.1016/j.abb.

2012.11.004.

119. Kim, K., Kim, S. J., Han, D., Jin, J., Yu, J., Park, K. S., Yu, H. G., and Kim, Y. (2013) Verification of multimark-

ers for detection of early stage diabetic retinopathy using multiple reaction monitoring, J. Proteome Res., 12,

1078-1089, https://doi.org/10.1021/pr3012073.

120. Loukovaara, S., Nurkkala, H., Tamene, F., Gucciardo, E., Liu, X., Repo, P., Lehti, K., and Varjosalo, M. (2015)

Quantitative proteomics analysis of vitreous humor from diabetic retinopathy patients, J. Proteome Res., 14,

5131-5143, https://doi.org/10.1021/acs.jproteome.5b00900.

121. Demircan,N., Safran, B. G., Soylu,M., Ozcan, A. A., and Sizmaz, S. (2006) Determination of vitreous interleukin-1

(IL-1) and tumour necrosis factor (TNF) levels in proliferative diabetic retinopathy, Eye (Lond.), 20, 1366-1369,

https://doi.org/10.1038/sj.eye.6702138.

122. Xiao, H., Xin, W., Sun, L. M., Li, S. S., Zhang, T., and Ding, X. Y. (2021) Comprehensive proteomic profiling of

aqueous humor proteins in proliferative diabetic retinopathy, Transl. Vis. Sci. Technol., 10, 3, https://doi.org/

10.1167/tvst.10.6.3.

123. Wang, H., Feng, L., Hu, J. W., Xie, C. L., and Wang, F. (2012) Characterisation of the vitreous proteome in pro-

liferative diabetic retinopathy, Proteome Sci., 10, 15, https://doi.org/10.1186/1477-5956-10-15.

124. Weber, S. R., Zhao, Y., Ma, J., Gates, C., da Veiga Leprevost, F., Basrur, V., Nesvizhskii, A. I., Gardner, T. W.,

and Sundstrom, J. M. (2021) A validated analysis pipeline for mass spectrometry-based vitreous proteomics:

new insights into proliferative diabetic retinopathy, Clin. Proteomics, 18, 28, https://doi.org/10.1186/s12014-

021-09328-8.

125. Yang, S., Xin, Z., Xiong, R., Zhu, Z., Li, H., Chen, Y., Zhong, Z., Du, L., Zhu, L. Z., Shang, X., Huang, W., Zhang, L.,

Chen, S., He, C., Tan, S., He, M., Congdon, N., Jonas, J. B., Tham, Y.-C., Cheng, C.-Y., and Wang, W. (2025) Pro-

teome atlas for mechanistic discovery and risk prediction of diabetic retinopathy, Nat. Commun., 16, 9636,

https://doi.org/10.1038/s41467-025-64634-1.

126. Montesano, G., Ometto, G., Higgins, B. E., Das, R., Graham, K. W., Chakravarthy, U., McGuiness, B., Young, I. S.,

Kee, F., Wright, D. M., Crabb, D. P., and Hogg, R. E. (2021) Evidence for structural and functional damage of the

SHEBARDINA et al.1338

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

inner retina in diabetes with no diabetic retinopathy, Invest. Ophthalmol. Vis. Sci., 62, 35, https://doi.org/10.1167/

iovs.62.3.35.

127. Ashraf, M., Cavallerano, J. D., Sun, J. K., Silva, P. S., and Aiello, L. P. (2021) Ultrawide field imaging in diabetic

retinopathy: exploring the role of quantitative metrics, J. Clin. Med., 10, 3300, https://doi.org/10.3390/jcm10153300.

128. Vujosevic,S., Toma, C., Nucci, P., Brambilla,M., and De Cillà, S. (2020) Quantitative color fundus autofluorescence

in patients with diabetes mellitus, J. Clin. Med., 10, 48, https://doi.org/10.3390/jcm10010048.

129. Sohn, E. H., van Dijk, H. W., Jiao, C., Kok, P. H. B., Jeong, W., Demirkaya, N., Garmager, A., Wit, F.,

Kucukevcilioglu, M., van Velthoven, M. E. J., DeVries, J. H., Mullins, R. F., Kuehn, M. H., Schlingemann, R. O.,

Sonka, M., Verbraak, F. D., and Abràmoff, M. D. (2016) Retinal neurodegeneration may precede microvascular

changes characteristic of diabetic retinopathy in diabetes mellitus, Proc. Natl. Acad. Sci. USA, 113, E2655-E2664,

https://doi.org/10.1073/pnas.1522014113.

130. McAnany, J. J., Persidina, O. S., and Park, J. C. (2022) Clinical electroretinography in diabetic retinopathy: a

review, Surv. Ophthalmol., 67, 712-722, https://doi.org/10.1016/j.survophthal.2021.08.011.

131. Pramanik, S., Chowdhury, S., Ganguly, U., Banerjee, A., Bhattacharya, B., and Mondal, L. K. (2020) Visu-

al contrast sensitivity could be an early marker of diabetic retinopathy, Heliyon, 6, e05336, https://doi.org/

10.1016/j.heliyon.2020.e05336.

132. Santos, A. R., Ribeiro, L., Bandello, F., Lattanzio, R., Egan, C., Frydkjaer-Olsen, U., García-Arumí, J., Gibson, J.,

Grauslund,J., Harding, S.P., Lang, G. E., Massin, P., Midena,E., Scanlon, P., Aldington, S.J., Simão, S., Schwartz, C.,

Ponsati, B., Porta, M., Costa, M., Hernández, C., Cunha-Vaz, J., and Simó, R. (2017) Functional and structural

findings of neurodegeneration in early stages of diabetic retinopathy: cross-sectional analyses of baseline data

of the EUROCONDOR project, Diabetes, 66, 2503-2510, https://doi.org/10.2337/db16-1453.

133. Vaughan, M., Denmead, P., Tay, N., Rajendram, R., Michaelides, M., and Patterson, E. (2025) How early can we

detect diabetic retinopathy? A narrative review of imaging tools for structural assessment of the retina, Graefes

Arch. Clin. Exp. Ophthalmol., 263, 2413-2425, https://doi.org/10.1007/s00417-025-06828-3.

134. Almas, S., Wahid, F., Ali, S., Alkhyyat, A., Ullah, K., Khan, J., and Lee, Y. (2025) Visual impairment prevention

by early detection of diabetic retinopathy based on stacked auto-encoder, Sci. Rep., 15, 2554, https://doi.org/

10.1038/s41598-025-85752-2.

135. Ting, D. S. W., Tan, K.-A., Phua, V., Tan, G. S. W., Wong, C. W., and Wong, T. Y. (2016) Biomarkers of diabetic

retinopathy, Curr. Diab. Rep., 16, 125, https://doi.org/10.1007/s11892-016-0812-9.

136. Gopalakrishnan, V., Purushothaman, P., and Bhaskar, A. (2015) Proteomic analysis of plasma proteins in dia-

betic retinopathy patients by two dimensional electrophoresis and MALDI-Tof-MS, J. Diabetes Complications,

29, 928-936, https://doi.org/10.1016/j.jdiacomp.2015.05.021.

137. Hajari, J. N., Ilginis, T., Pedersen, T. T., Lønkvist, C. S., Saunte, J. P., Hofsli, M., Schmidt, D. C., Al-abaiji, H. A.,

Ahmed, Y., Bach-Holm, D., Kessel, L., Kolko, M., Bertelsen, M., Larsen, L. M., Sørensen, F., Forman, J. L.,

Olsen, D. A., Rosenberg, T., Brandslund, I., and Slidsborg, C. (2025) Novel blood-biomarkers to detect retinal

neurodegeneration and inflammation in diabetic retinopathy, Int. J. Mol. Sci., 26, 2625, https://doi.org/10.3390/

ijms26062625.

138. Martínez-Santos, M., Ybarra, M., Pires, M. E., Ceresoni, C., Martínez-López, E., Sancho-Pelluz, J., Oltra, M., and

Barcia, J. M. (2025) Circulating microRNAs as biomarkers for diabetic retinopathy stage identification: a DTA

systematic review and meta-analysis, PLoS One, 20, e0335434, https://doi.org/10.1371/journal.pone.0335434.

139. Zou, H.-L., Wang, Y., Gang, Q., Zhang, Y., and Sun, Y. (2017) Plasma level of miR-93 is associated with high-

er risk to develop type 2 diabetic retinopathy, Graefes Arch. Clin. Exp. Ophthalmol., 255, 1159-1166, https://

doi.org/10.1007/s00417-017-3638-5.

140. Gospodarczyk, N., Martyka, A., Błaszczyk, U., Czuj, W., Piekarska, J., Wylęgała, E., and Nowińska, A. (2025)

Tear fluid biomarkers in diabetic ocular surface disease: a systematic review, J. Clin. Med., 14, 6958, https://

doi.org/10.3390/jcm14196958.

141. Hu, L., Zhang, T., Ma, H., Pan, Y., Wang, S., Liu, X., Dai, X., Zheng, Y., Lee, L. P., and Liu, F. (2022) Discovering

the secret of diseases by incorporated tear exosomes analysis rapid-isolation system: iTEARS, ACS Nano, 16,

11720-11732, https://doi.org/10.1021/acsnano.2c02531.

142. Regu, V. R., Swain, R. P., Pattnaik, L., and Subudhi, B. B. (2025) Topical delivery of anti-VEGF macromolecules

for retinopathy: a review, Int. J. Biol. Macromol., 312, 144151, https://doi.org/10.1016/j.ijbiomac.2025.144151.

143. Rafael, D., Guerrero, M., Marican, A., Arango, D., Sarmento, B., Ferrer, R., Durán-Lara, E. F., Clark, S. J., and

Schwartz, S. (2023) Delivery systems in ocular retinopathies: the promising future of intravitreal hydrogels as

sustained-release scaffolds, Pharmaceutics, 15, 1484, https://doi.org/10.3390/pharmaceutics15051484.

144. Pieramici, D. J., Awh, C. C., Chang, M., Emanuelli, A., Holekamp, N. M., Hu, A. Y., Suñer, I. J., Wykoff, C. C.,

Brittain, C., Howard, D., Quezada-Ruiz, C., Santhanakrishnan, A., and Latkany, P. (2025) port delivery system

MOLECULAR MECHANISMS OF DIABETIC RETINOPATHY 1339

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

with ranibizumab vs monitoring in nonproliferative diabetic retinopathy without macular edema: the Pavilion

randomized clinical trial, JAMA Ophthalmol., 143, 317-325, https://doi.org/10.1001/jamaophthalmol.2025.0001.

145. Seah, I., Zhao, X., Lin, Q., Liu, Z., Su, S. Z. Z., Yuen, Y. S., Hunziker, W., Lingam, G., Loh, X. J., and Su, X. (2020)

Use of biomaterials for sustained delivery of anti-VEGF to treat retinal diseases, Eye (Lond.), 34, 1341-1356,

https://doi.org/10.1038/s41433-020-0770-y.

146. Teng, X., Yuan, Z., Li, M., Sun, L., Xiong, X., Sha, X., Liu, L., Yu, G., Tu, L., Chan, L., and Zhong, J. (2026) Charge-

flip nanoparticles loaded with TAK1 inhibitors inhibit retinal neovascularization, J. Nanobiotechnol., 24, 199,

https://doi.org/10.1186/s12951-026-04078-x.

147. Mu, H., Wang, Y., Chu, Y., Jiang, Y., Hua, H., Chu, L., Wang, K., Wang, A., Liu, W., Li, Y., Fu, F., and Sun, K.

(2018) Multivesicular liposomes for sustained release of bevacizumab in treating laser-induced choroidal neo-

vascularization, Drug Deliv., 25, 1372-1383, https://doi.org/10.1080/10717544.2018.1474967.

148. Odio-Herrera, M., Orozco-Loaiza, G., and Wu, L. (2025) Gene therapy in diabetic retinopathy and diabetic mac-

ular edema: an update, J. Clin. Med., 14, 3205, https://doi.org/10.3390/jcm14093205.

149. Chawan-Saad, J., Wu, M., Wu, A., and Wu, L. (2019) Corticosteroids for diabetic macular edema, Taiwan J. Oph-

thalmol., 9, 233-242, https://doi.org/10.4103/tjo.tjo_68_19.

150. Kim, J., Kim, C.-S., Moon, M. K., and Kim, J. S. (2015) Epicatechin breaks preformed glycated serum albumin

and reverses the retinal accumulation of advanced glycation end products, Eur. J. Pharmacol., 748, 108-114,

https://doi.org/10.1016/j.ejphar.2014.12.010.

151. Maeda, S., Matsui, T., Ojima, A., Suematsu, M., Kaseda, K., Higashimoto, Y., Yamakawa, R., and Yamagishi, S.

(2015) DNA aptamer raised against advanced glycation end products prevents abnormalities in electroretino-

grams of experimental diabetic retinopathy, Ophthalmic Res., 54, 175-180, https://doi.org/10.1159/000440768.

152. Ye, X., Fung, N. S. K., Lam, W. C., and Lo, A. C. Y. (2024) Nutraceuticals for diabetic retinopathy: recent advances

and novel delivery systems, Nutrients, 16, 1715, https://doi.org/10.3390/nu16111715.

153. Rusciano, D., and Bagnoli, P. (2025) The controversial role of nutraceuticals vs. drugs in proliferative retinopa-

thies, Front. Neurosci., 19, 1727089, https://doi.org/10.3389/fnins.2025.1727089.

154. Lunegova, D. A., Gvozdev, D. A., Senin, I. I., Gudkova, V. R., Sidorenko, S. V., Tiulina, V. V., Shebardina, N. G.,

Yakovleva, M. A., Feldman, T. B., Ramonova, A. A., Moysenovich, A. M., Semenov, A. N., Zernii, E. Yu.,

Maksimov, E. G., Sluchanko, N. N., Kirpichnikov, M. P., and Ostrovsky, M. A. (2025) Antioxidant properties of

the soluble carotenoprotein AstaP and its feasibility for retinal protection against oxidative stress, FEBS J.,

292, 355-372, https://doi.org/10.1111/febs.17335.

155. Arkhipchenko, A. A., Semenov, A. N., Chesalin, D. D., Sidorenko, S. V., Bodunova, D. V., Gorokhov, E. S.,

Yakovleva,M. A., Feldman, T.B., Moysenovich, A.M., Senin, I.I., Shebardina, N. G., Tiulina, V. V., Ramonova,A. A.,

Andreev, V. S., Morozov, P. V., Bilan, D. S., Ilyinsky, N. S., Zernii, E. Y., Maksimov, E. G., Ostrovsky, M. A., and

Kirpichnikov, M. P. (2026) Photooxidation dynamics of lipofuscin in the presence of carotenoid-binding pro-

tein AstaP: fluorescence lifetime imaging and pigment composition analysis, J.Phys. Chem.B, 130, 2974-2986,

https://doi.org/10.1021/acs.jpcb.5c06621.

156. Ge, Y., Zhang, A., Sun, R., Xu, J., Yin, T., He, H., Gou, J., Kong, J., Zhang, Y., and Tang, X. (2020) Penetra-

tin-modified lutein nanoemulsion gel for the treatment of age-related macular degeneration, Expert Opin.

Drug Deliv., 17, 603-619, https://doi.org/10.1080/17425247.2020.1735348.

157. Nath, M., Shan, Y., Myers, A. M., and Fort, P. E. (2021) HspB4/αA-Crystallin Modulates Neuroinflamma-

tion in the Retina via the Stress-Specific Inflammatory Pathways, J. Clin. Med., 10, 2384, https://doi.org/

10.3390/jcm10112384.

158. Kim, D., Lewis, C. S., Sarthy, V. P., and Roy, S. (2020) High-glucose-induced Rab20 upregulation disrupts

gap junction intercellular communication and promotes apoptosis in retinal endothelial and Müller cells:

implications for diabetic retinopathy, J. Clin. Med., 9, 3710, https://doi.org/10.3390/jcm9113710.

159. Antonetti, D. A., Silva, P. S., and Stitt, A. W. (2021) Current understanding of the molecular and cellu-

lar pathology of diabetic retinopathy, Nat. Rev. Endocrinol., 17, 195-206, https://doi.org/10.1038/s41574-

020-00451-4.

160. Jiang, Q., Lyu, X.-M., Yuan, Y., and Wang, L. (2017) Plasma expression: an indicator for the severity of Type 2

diabetes with diabetic retinopathy, Biosci. Rep., 37, BSR20160589, https://doi.org/10.1042/BSR20160589.

161. Gu, C., Zhang, H., and Gao, Y. (2021) Adipose mesenchymal stem cells-secreted extracellular vesicles con-

taining microRNA-192 delays diabetic retinopathy by targeting ITGA1, J. Cell Physiol., 236, 5036-5051, https://

doi.org/10.1002/jcp.30213.

162. Ebrahim, N., El-Halim, H. E. A., Helal, O. K., El-Azab, N. E.-E., Badr, O. A. M., Hassouna, A., Al Saihati, H. A.,

Aborayah, N. H., Emam, H. T., El-wakeel, H.S., Aljasir, M., El-Sherbiny, M., Sarg, N.A. S., Shaker, G. A., Mostafa, O.,

Sabry, D., Fouly, M. A. K., Forsyth, N. R., Elsherbiny, N. M., and Salim, R. F. (2022) Effect of bone marrow

SHEBARDINA et al.1340

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

mesenchymal stem cells-derived exosomes on diabetes-induced retinal injury: implication of Wnt/b-catenin sig-

naling pathway, Biomed. Pharmacother., 154, 113554, https://doi.org/10.1016/j.biopha.2022.113554.

163. Lv, Y., Zhai, C., Sun, G., and He, Y. (2024) Chitosan as a promising materials for the construction of nano-

carriers for diabetic retinopathy: an updated review, J. Biol. Eng., 18, 18, https://doi.org/10.1186/s13036-

024-00414-7.

164. Badr, G. A., Tang, J., Ismail-Beigi, F., and Kern, T. S. (2000) Diabetes downregulates GLUT1 expression in the

retina and its microvessels but not in the cerebral cortex or its microvessels, Diabetes, 49, 1016-1021, https://

doi.org/10.2337/diabetes.49.6.1016.

165. Liu, Y., and Wu, N. (2021) Progress of nanotechnology in diabetic retinopathy treatment, Int. J. Nanomed., 16,

1391-1403, https://doi.org/10.2147/IJN.S294807.

166. Kazakova, K. A., Moisenovich, A. M., Ramonova, A. A., and Bogush, V. G. (2025) Development of bioengineered

constructs based on recombinant spideroin for peripheral nervous system regeneration [in Russian], Biotech-

nologiya, 41, 131-133, https://doi.org/10.56304/s0234275825040386.

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published

maps and institutional affiliations. AI tools may have been used in the translation or editing of this article.