ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 8, pp. 1432-1448 © Pleiades Publishing, Ltd., 2026.
1432
REVIEW
Experimental Models of Acute Liver Failure in Mice:
From Pathogenesis and Inflammatory Cascades
to the Role of Intestine
Fedor A. Sysonov
1,2,3,a
*, Ekaterina A. Gorshkova
1,2,3
,
Konstantin E. Menshikov
1,2,3
, Marina S. Drutskaya
1,2
, Sergey A. Nedospasov
1,2,3
,
and Ekaterina O. Gubernatorova
1,2,3,b
*
1
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
2
Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
3
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
a
e-mail: fsysonov@yandex.ru
b
e-mail: ekaterina.gubernatorova412@gmail.com
Received July 9, 2026
Revised July 31, 2026
Accepted August 3, 2026
Abstract— Acute liver failure (ALF) is a severe pathological condition with high mortality, arising from di-
verse etiologies and involving multiple pathogenetic mechanisms. ALF is often accompanied by multi-organ
failure due to infectious complications. Because of disease’s rapid progression, clinical studies of ALF remain
limited, making the search for novel therapeutic strategies targeting specific molecular pathways and bio-
chemical cascades a pressing task. Preclinical in vivo models are unique tools for reproducing individual
aspects of ALF development. However, there is still no consensus on the gold-standard experimental animal
model that fully captures ALF pathogenesis. This review systematically categorizes existing mouse models
of ALF, outlining their advantages and with respect to the translational applicability of the data obtained.
Among these models, we highlight the LPS/D-GalN model as the most reliable in reproducing key stages of
ALF development complicated by bacterial infection. Using this model as an example, we describe the known
stages of pathogenesis, supported by the experiments with pharmacologically active substances and the use
of various genetically modified mouse lines. Finally, special attention is given to the intestine as an organ
that sustains significant damage during ALF progression in both clinical cases and most animal models.
DOI: 10.1134/S000629792660239X
Keywords: acute liver failure, liver failure, mouse models, inflammation, LPS/D-GalN, intestine
* To whom correspondence should be addressed.
INTRODUCTION
Acute liver failure (ALF) is a rapidly progressing
liver injury caused by xenobiotics (including drugs),
ethanol, or hepatotropic viruses. The rapid progres-
sion of the disease complicates the study of ALF in
clinical settings, resulting in a limited arsenal of effec-
tive therapeutic strategies. Currently, most therapeutic
approaches focus on symptom relief and improving
the patient’s general condition, while liver transplan-
tation remains the only effective method for restoring
liver function in cases of extensive damage. At pres-
ent, one in 25 deaths worldwide is associated with
some form of liver damage [1], indicating absence of
an effective therapeutic approach. Meanwhile, a large
number of animal models reproduce individual stag-
es of ALF development in the context of various eti-
ologies. However, given the wide range of etiologies,
the lack of consensus on the most suitable animal
model for ALF, and multistep mechanism of hepato-
toxicity development, it is necessary to systematize
the available results obtained from in vivo models
and identify individual stages of ALF pathogenesis.
Additionally, the most relevant animal model for ex-
ploring new therapeutic approaches must be deter-
mined.
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CLINICAL COURSE
OF ALF DEVELOPMENT IN HUMANS
Regardless of the initial causes of ALF, the key
event in its pathogenesis is hepatocyte death [2]. Di-
agnostic criteria include impaired blood coagulation
and hepatic encephalopathy, both associated with im-
paired liver function or hepatocyte death. Liver fail-
ure resulting from the massive hepatocyte necrosis
leads to hyperammonemia, inflammation, toxin ac-
cumulation, and could lead to multiorgan failure [3].
Biochemical markers of ALF development include
systemic levels of aminotransferases, alkaline phos-
phatase, and albumin. Alanine aminotransferase (ALT)
is a more specific marker of liver damage, as it pri-
marily accumulates in hepatocytes, whereas aspartate
aminotransferase (AST) is present in the cells of other
parenchymal organs [4]. Elevated levels of alkaline
phosphatase (ALP) correlate with poor prognosis in
patients with ALF, potentially due to the strong pro-in-
flammatory burden[5]. Meanwhile, systemic albumin
levels decrease in ALF due to increased rate of bind-
ing to small molecules, including those of bacterial
origin, and activation of its antioxidant activity [6].
In Russia and Asian countries, viral diseases are
the primary cause of ALF, unlike Western countries,
where acetaminophen (paracetamol) poisoning is
the leading cause [7, 8]. Early identification of the
cause of ALF is critical for prescribing specific thera-
py: N-acetylcysteine for pharmacological intoxication,
lamivudine for hepatitis B virus (HBV), or steroids
for autoimmune hepatitis [9]. Reduced bone mar-
row function in ALF leads to immune suppression,
increasing the risk of infectious complications [10].
Infections complications are common in pathogenesis
of ALF (occurring in up to 80% of clinical cases) [11,
12], with most infections being bacterial, although
fungal and viral infections also have been observed.
ALF treatment is conducted in intensive care
units with continuous monitoring of vital parame-
ters. Most therapeutic strategies focus on the relief of
symptoms and prevention of multi-organ failure [9].
Extracorporeal methods used to cleanse blood of tox-
ins and correct its cellular and chemical composition
outside the body could prolong the patient’s life until
liver transplantation, which remains the gold stan-
dard for ALF treatment [13, 14].
The most widely used system for assessing the
need for liver transplantation is the King’s College
Criteria, developed in 1989 based on 588 ALF cases
treated at King’s College Hospital between 1973 and
1985 [15]. This approach divides patients into two
groups: ALF associated with acetaminophen poison-
ing and ALF developing from other causes. In the
cases of acetaminophen poisoning, poor prognosis is
assumed in the patients with an arterial pH below 7.3
or in those who simultaneously exhibit elevated In-
ternational Normalized Ratio (INR) above 6.5, serum
creatinine above 300 µmol/L, and presence of enceph-
alopathy. In the cases where ALF development is not
associated with acetaminophen poisoning, the King’s
College Criteria propose a broader range of markers
associated with the poor prognosis: patient age, se-
rum bilirubin levels, disease duration, INR levels, and
concurrent drug poisoning. The difference between
the groups is related to the rate of development and
duration of coagulation disorders: in the patients
with acetaminophen poisoning, acute coagulopathy is
observed, which decreases on the second day, where-
as in the patients with ALF of other etiologies, high
INR levels persist for a longer period [16].
The pathogenesis of ALF often leads to multiorgan
damage, occurrence of which, according to the retro-
spective clinical analysis, is associated with thrombo-
cytopenia and impaired blood coagulation [16]. Pa-
tients could develop complications in the respiratory,
cardiovascular, nervous, and digestive systems [17].
Increased intestinal permeability is a common fea-
ture of ALF regardless of etiology, observed in the
clinical cases caused by alcohol intoxication [18, 19],
acetaminophen poisoning [20], or viral infection [21].
Any disruption of intestinal homeostasis could mod-
ulate the state of immune system and development
of inflammatory response due to the endogenous
microbiota. Thus, influence of the intestine on ALF
pathogenesis could be an interesting direction for the
development of new therapeutic approaches.
Due to the high rate of disease progression, mul-
tiorgan failure, and lack of universal methods for ef-
fective body detoxification, studying of ALF pathogen-
esis in clinical research is limited almost exclusively
to the retrospective approaches. The use of animal
models is therefore a promising direction for the de-
velopment of new approaches to ALF therapy and
studying inter-organ communication [22, 23]. Among
animal models, mouse models of ALF are the most
common, with the advantage of using genetically
modified strains for detailed studies of pathogenesis
using reverse genetics approaches.
MOUSE MODELS OF ALF
Three groups of experimental protocols aim to
reproduce clinical course of ALF development in
mice: surgical, pharmacological, and immunogenic.
Despite the wide variety of experimental approaches,
no consensus exists regarding which model that most
successfully replicates the key stages of pathogenesis
and symptomatology of the human disease (Fig. 1).
Although mice and rats remain the most common-
ly used species for modeling ALF, their small size
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Fig. 1. Models of acute hepatotoxicity. Mouse models of ALF: surgical, pharmacological, and immunogenic. Each model re-
produces a specific etiology of liver damage development, while all lead to similar consequences at the biochemical and mo-
lecular (ALT/AST, DAMPs), cellular (hepatocyte necrosis, immune cell recruitment), and systemic (multiorgan failure) levels.
precludes adequate recapitulation of the metabolic al-
terations and disease dynamics observed in humans.
SURGICAL MODELS
Models of total or partial liver resection leading
in either permanent or transient organ dysfunction
have limited clinical relevance. Removal of part of
the liver in experimental animals is frequently not
lethal due to the organ’s high regenerative poten-
tial [24]. Total hepatectomy, although causing com-
plete loss of liver function, cannot be a fully reli-
able model of ALF because patients undergoing liver
transplantation are without a liver for an average of
70 min, and no correlation between the duration of
this period and survival has been identified [25]. The
consequences of partial liver resection depend direct-
ly on the extent of the removed tissue: 90% hepatec-
tomy leads to 100% lethality in mice within a day,
while removal of 70% of the organ does not cause
death in the experimental animals [26]. There is evi-
dence of ALF occurrence after partial liver resection
in the patients [27]. However, owing to the absence of
a toxic insult, this model, without additional modifi-
cations, is more suitable for studying liver regenera-
tion than for modeling ALF [28].
Portosystemic anastomosis (an artificial connec-
tion between the portal vein and inferior vena cava)
allows the liver to be excluded from the systemic
blood flow. However, to simulate severe liver dam-
age, additional ligation of the hepatic artery is re-
quired [29], making the effect irreversible. Although
this approach preserves the organ in the body, it caus-
es ischemic necrosis, which only partially reproduc-
es the ALF pathogenesis. The widely used preclinical
model of ALF– liver ischemia-reperfusion [30] – does
not require complex surgical intervention or organ
removal. The degree of hepatocyte damage directly
depends on the duration of ischemia and the inten-
sity of reperfusion, which diminishes reproducibili-
ty of the results. Thus, surgical models cannot fully
recapitulate clinical features of ALF development, as
they lack the key factor in most cases of the disease–
the effect of an exogenous toxic agent. Moreover, the
utility of surgical models for fundamental and clinical
research is complicated by their low methodological
reproducibility.
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PHARMACOLOGICAL MODELS
Pharmacological models of ALF are based on
the compounds that exert a toxic effect on the liv-
er: acetaminophen, carbon tetrachloride (CCl
4
), and
D-galactosamine. Among the experimental models,
acetaminophen (APAP)-induced ALF most accurate-
ly reproduces clinical picture of the drug-induced
liver injury. High doses of acetaminophen lead to
formation of toxic metabolic products such as N-ace-
tyl-p-benzoquinone imine (NAPQI), which cause he-
patocyte necrosis [31, 32]. Under normal conditions,
NAPQI is quickly neutralized by glutathione (GSH).
However, in the cases of severe acetaminophen
overdose accompanied by the reduction in the GSH
pool, toxic metabolites inflict critical hepatocellular
damage [33].
In addition to the models of drug-induced (ac-
etaminophen-induced) hepatotoxicity, which simulate
common clinical scenarios of ALF, other experimental
approaches employ chemical agents such as CCl
4
or
D-galactosamine. However, many of these reproduce
only isolated aspects of pathogenesis, limiting their
clinical applicability for studying complex dynamics
of the disease [34]. The action of both CCl
4
and acet-
aminophen is mediated by cytochrome P450, which
converts them into toxic compounds [35, 36]. Thus,
any effect on P450 directly prior to the induction of
these experimental models may distort results or de-
crease their reliability [37].
Finally, the third most common pharmacological
model is D-galactosamine-mediated ALF [38, 39]. Tis-
sue specificity of D-galactosamine (D-GalN) is deter-
mined by its metabolism via enzymes of the Leloir
pathway, which are most highly expressed in the liv-
er [40]. D-GalN depletes the uridine triphosphate pool
in hepatocytes, disrupting RNA synthesis and leading
to transcriptional suppression, causing liver dysfunc-
tion at high doses [41-43]. Often, immune-activating
agents, such as lipopolysaccharide (LPS) or tumor
necrosis factor (TNF), are administered simultaneous-
ly to accelerate the effect of D-GalN on hepatocytes
[44, 45].
Thus, pharmacological models are the most rel-
evant for reliable reproduction of the ALF induc-
tion observed in the drug-induced or other poison-
ings. However, the effects observed in these models
could depend on the differences in metabolism and
nature of the immune response between the mod-
el animals and humans. Additionally, relevance of
the results obtained in pharmacological models of
ALF is diminished because they exclusively repro-
duce the sterile inflammation accompanying he-
patocyte death, whereas in clinical practice, ALF
is usually accompanied by additional infectious
stimuli.
IMMUNOGENIC MODELS OF HEPATOTOXICITY
Unlike surgical and pharmacological models,
which aim to reproduce clinical picture during tem-
porary organ hypoxia or poisoning, infectious ap-
proaches model ALF development in the context of
liver damage caused by infection. The models that
most closely approximate the clinical picture of ALF
in humans are infectious models, particularly viral
infection models. Among them, two approaches could
be distinguished. Use of species-specific viruses in
wild-type experimental animals. For mice the mouse
hepatitis virus 3 is used, which causes acute hemor-
rhagic necrotic hepatitis with high lethality, mimick-
ing ALF due to its tropism for hepatocytes and induc-
tion of coagulopathy [46].
Genetic editing approaches that result into ALF
development following exposure to the viruses that
do not specifically target liver under normal condi-
tions [47, 48]. For example, the herpes simplex virus
type 1 (HSV-1) could cause massive liver necrosis in
mice with deficiency in MAVS (mitochondrial anti-
viral-signaling protein) or IFN receptors (IFNAR1,
IFNGR).
To study the human ALF-associated viruses (hep-
atitis viruses, cytomegalovirus, Epstein–Barr virus,
etc.) in mouse models, it is necessary to generate
genetically modified, including humanized, models
(e.g., NSG or AFC8-hu HSC/Hep). Such mice, carrying
human hepatocytes or immune cells, become suscep-
tible to the infections caused by HCV, HBV, CMV, or
EBV. Following viral replication, the animals develop
inflammation, exhibit elevated ALT levels, and show
leukocyte infiltration of the liver – manifestations
similar to those of the pathology in humans [49-52].
Another widely used model of immunogenic
ALF is intravenous administration of concanavalin A
(ConA). ConA induces the expansion of the activated
T cells, which, subsequently attack the liver, causing
autoimmune tissue damage [53]. In addition, due to
its lectin nature, ConA can promote the formation of
thrombi and erythrocyte aggregates in the blood [54],
which enhances inflammation but complicates inter-
pretation of the results in context of ALF modeling.
Moreover, concanavalin A, being a superantigen that
binds MHC class II and the T-cell receptor, models
a specific case of autocrine attack on the liver by
the immune cells, rather than the full spectrum of
inflammation. The tropism of ConA for the liver is
determined by the intravenous route of administra-
tion, as the substance is transported in the blood and
accumulates predominantly in the hepatic tissue [55].
Thus, immunogenic approaches aimed solely at
activating immune system during the viral or auto-
crine inflammation are of limited clinical relevance
due to the highly artifactual nature of the models
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themselves, as well as specificity of the modeled eti-
ology. This indicates the need for a more compre-
hensive approach in modeling ALF associated with
inflammatory processes.
Recently, a growing number of studies have ad-
dressed inter-organ interactions in the context of clin-
ical picture of the acute inflammation in hepatotox-
icity. For example, it has been shown that induction
of polymicrobial sepsis by surgical disruption of the
cecum integrity (cecal ligation and puncture, CLP) in
combination with thioacetamide exposure leads to
the significant loss of liver functionality [56]. Mouse
models of sepsis can be employed to study the patho-
genesis of ALF associated with immune system acti-
vation, while induction of acute inflammation with
simultaneous administration of a hepatotoxin is a
classic approach for studying ALF in mice. The most
common model of this type is simultaneous adminis-
tration of lipopolysaccharide– an activator of system-
ic inflammation – and D-galactosamine (LPS/D-GalN-
induced hepatotoxicity) to mice [45]. This model is
distinguished by its simplicity and high reproducibil-
ity, more accurately reflecting development of acute
hepatotoxicity against the background of bacterial in-
fections, which makes it representative for studying
the mechanisms of ALF observed in clinical practice.
Polymicrobial inflammation itself can lead to the de-
velopment of liver damage, and disruption of the in-
testinal barrier in the LPS/D-GalN model contributes to
an elevated overall inflammatory background [57-59].
Similar approaches to modeling antigen load in the
context of hepatotoxicity were demonstrated for the
acetaminophen-dependent liver damage: when a
non-lethal dose of APAP was administered along with
LPS, all experimental mice died [60]. The combination
of immunogenic and pharmacological models, due to
their high similarity to clinical cases (where infec-
tious complications occur in 80% of cases), may be
considered the most successful strategy for generat-
ing results that are translatable to clinical practice.
In summary, among the variety of mouse models
of ALF (Table S1 in the Online Resource 1), the com-
bined approaches that integrate immunogenic and
pharmacological models most closely approximate the
clinical picture of ALF pathogenesis with infectious
complications. The most studied among these models
is the LPS/D-GalN-induced ALF.
MECHANISMS OF THE LPS/D-GalN-INDUCED
ALF DEVELOPMENT
As one of the most extensively studied and wide-
ly employed models, the LPS/D-GalN-induced ALF suc-
cessfully reproduces not only liver injury caused by
D-GalN but also the consequences of the additional
bacterial load, which occurs in the vast majority of
clinical cases. This combination of bacterial antigen
with a hepatotoxin distinguishes the LPS/D-GalN mod-
el from the other principal animal models of ALF
(Table S1 in the Online Resource 1). The primary
markers of the LPS/D-GalN-induced ALF development
are increased levels of transaminases in the blood of
the experimental animal, increased systemic produc-
tion of tumor necrosis factor (TNF), and hepatocyte
death [61]. The presence of these markers indicates
a close resemblance to the picture observed in the
patients with ALF of diverse etiologies [62-64].
The mechanisms of LPS/D-GalN-induced ALF de-
velopment have been investigated using various ge-
netically modified mouse strains, as well as bioactive
substances that target individual stages of pathogen-
esis. Using reverse genetics approaches in the mouse
models, the key role of TNF as a central mediator in
the LPS/D-GalN-induced ALF model has been demon-
strated [65]. Moreover, further studies have clarified
that the cellular source of TNF responsible for lethal-
ity is myeloid cells [66].
The mechanism of by which TNF directly effects
has also been elucidated: due to the preliminary
sensitization of liver cells by D-GalN, transcription
processes are disrupted as a result of depletion of
the UTP pool – the main source of uridine for the
template RNA synthesis. Simultaneously, activation of
TNFR1 on the cell surface in the context of blocked
transcription, leads to activation of pro-caspase 8,
which ultimately initiates apoptotic or necroptotic
cell death. Mice with genetic inactivation of TNFR1
are resistant to LPS/D-GalN-induced ALF. Experiments
using bone marrow chimeras have shown that the
TNFR1-mediated signaling is critical in the cells of
non-hematopoietic origin [65, 67]. Mice deficient in
TLR4 exhibit resistance to LPS toxicity [68]. At low
doses of LPS and D-GalN, the mice with the knockout
of Tlr4 in myeloid cells are protected from death in
the LPS/D-GalN-induced ALF model [69]. In addition
to the data on TLR4/TNF/TNFR1 intercellular signal
transduction, the key role of resident macrophages
has been demonstrated: their depletion achieved
by administration of the clodronate-containing lipo-
somes, increases resistance of the mice to LPS/D-GalN-
induced ALF [70].
Thus, the TLR4/TNF/TNFR1 axis plays a key role
in the development of inflammation that culminates
in the lethal outcome in the LPS/D-GalN-induced ALF
model: activation of TLR4 on myeloid cells leads to
the sharp increase in the systemic TNF production,
which, in turn, acts upon hepatocytes via TNFR1. Con-
currently, studies with various strains of genetically
modified mice have revealed a significant contribu-
tion of other inflammation-associated mechanisms,
including recruitment of immune cells to the liver,
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Table 1. Mediators of inflammation, chemotaxis of immune cells, and hepatocyte metabolism in the LPS/D-GalN-induced ALF model
Stages of
pathogenesis
Mouse strain Observed effects Function of target molecule Reference
Main axis of
inflammation
development
Tnf-knockout (C57BL/6) complete protection, 100% survival TNF is a central mediator of LPS/D-GalN ALF
development, leading to hepatocyte death
through interaction with TNFR1
[65]
Tnf-knockout in myeloid cells
(LysM
Cre
TNF
fl/fl
; C57BL/6)
[66]
Tlr4-knockout (C57BL/6) TLR4 is a receptor of the innate immune
system that recognizes LPS
[68, 69]
Tlr4-knockout in myeloid cells
(LysM
Cre
TLR4
fl/fl
; C57BL/6)
[69]
Tnfrsf1a-knockout (C57BL/6) TNFR1 is a receptor for TNF, widely
expressed on most cells in the body
[65]
Bcl3-knockout in hepatocytes
(BCL-3Hep; C57BL/6)
reduced lethality, lower systemic levels
of ALT, AST, TNF
BCL3 is an important regulator of NF-κB
activation, activating TNF-dependent
hepatocyte death by regulating RIP1
deubiquitination
[44, 71]
Recruitment
of cells to the
liver
IL-17AIl17a-knockout (C57BL/6) reduced lethality, lower systemic levels
of ALT and TNF
IL-17A is an important cytokine involved
in neutrophil recruitment to tissues
[72]
Lect2-knockout (BALB/cA) reduced lethality, lower levels
of pro-inflammatory cytokines in blood
LECT2 is a protein produced mainly by
the liver, involved in neutrophil recruitment
[73]
Hepatocyte
metabolism
Cav1-knockout (C57BL/6) protection from lethal ALF development,
reduced histological damage in the liver,
systemic production of pro-inflammatory
cytokines, and local expression of Tnf
in the liver. Reduced TLR4 expression
on the surface of F4/80+ cells and NF-κB
activation in them
caveolin-1 regulates glucose and lipid
metabolism, hepatocyte proliferation,
and mitochondrial cholesterol levels.
It is the main protein of caveolae
[74]
Ninj1-knockout in hepatocytes
(albumin
Cre
Ninj1
fl/fl
; C57BL/6)
reduced levels of ALT and AST, reduced
histological damage to liver tissue,
and intra-tissue concentration of TNF
NINJ1 is a cell adhesion protein whose
expression increases during inflammation.
It can interact with xCT, a channel for cystine
transport into cells, reducing its activity
[75, 76]
Pkm2-knockout in myeloid
cells (LysM
Cre/wt
PKM2
fl/fl
;
C57BL/6)
reduced levels of ALT and histological
damage to liver tissue
PKM2 (pyruvate kinase M2) is a key enzyme
in glycolysis, catalyzing the conversion
of phosphoenolpyruvate to pyruvate
[77]
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Table 1 (cont.)
Stages of
pathogenesis
Mouse strain Observed effects Function of target molecule Reference
Specific
stages of
pathogenesis
Il19-knockout (C57BL/6
with backcross to BALB/c)
elevated levels of ALT, expression
of Ccl2 in the liver, enhanced
histological damage to liver tissue
in IL-19-KO mice
IL-19 has an anti-inflammatory effect
on monocytes and macrophages
[78]
Adipoq-knockout (C57BL/6) increased lethality, elevated systemic
levels of TNF, expression of Tnf
in the liver
adiponectin can suppress NF-κB activation,
reducing the pro-inflammatory response
of immune cells
[79]
Il1r1-knockout in hepatocytes
(albumin
Cre
IL-1R
fl/fl
; C57BL/6)
reduced levels of ALT, AST,
and LDH, histological damage
to liver tissue, production
of pro-inflammatory cytokines,
and reduced lethality
IL-1R1 is a receptor for pro-inflammatory
cytokines (IL-1a and IL-1b); signaling through
it leads to NF-κB activation
[80]
Rnf115-knockout (C57BL/6) increased survival, reduced levels
of ALT and AST, reduced histological
damage to liver tissue
RNF115 is an E3 ubiquitin ligase involved
in autophagy
[81]
Note. Results obtained from the mouse strains with knockouts of various genes in the LPS/D-GalN-induced ALF model indicate a number of key mechanisms:
1) The TLR4/TNF/TNFR1 axis is central to the pathogenesis and development of lethality, as inactivation of any of the genes encoding these proteins leads to complete
protection from lethality. 2) Recruitment of immune cells to the liver mediated by chemokines (LECT2, IL-17A) enhances local inflammation in the tissue, and deletion
of the genes encoding these chemoattractants reduces liver damage. 3)Hepatocyte metabolism is a determining factor in the ALF development: deletion of ninjurin-1 or
caveolin-1 leads to the improved general condition and provides partial protection from death in the LPS/D-GalN-induced ALF model. 4) The overall pro-inflammatory
background determines the nature and rate of ALF pathogenesis development: reduced NF-κB activation, suppression of inflammatory cytokine production, or inhibition
of autophagy affects severity of the liver damage in the LPS/D-GalN-induced ALF model.
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Table 2. Molecular targets of ALF pathogenesis identified in the LPS/D-GalN model using pharmacological
interventions
Category Substance Molecular targets Effects on the liver Reference
Effect on cell
death
luteolin c-Jun, apoptosis reduced hepatocyte
death
[82]
caspase-1 inhibitor,
YVAD-CMK
caspase-1, apoptosis complete protection even
at high doses of LPS
[83]
alpinetin Nrf2/SLC7A11/GPX4,
pyroptosis inhibition
protection
from LPS/D-GalN
[84]
Effect on
inflammation
activation
mangiferin HO-1, NF-κB, inflammation dose-dependent
protection, reduced
lethality
[70]
resveratrol SIRT1, NF-κB blocking inflammation
when SIRT1 is inhibited
[85]
LPS
preconditioning
TLR4, NF-κB, IRAK-1 endotoxin tolerance [86]
p-coumaric acid NF-κB reduced lipid
peroxidation
[87]
atractylenolide I MAPK/IRF5 activation
pathways
reduced ALT/AST,
necrosis
[88]
MYSTI-2 TNF produced by F4/80
+
cells
Complete protection [89]
Effect on
metabolism/other
aspects
orientin PFKL (inhibition
of glycolysis and
inflammation)
reduced liver damage [90]
tamoxifen unknown restoration
of antioxidant pool
[91]
puerarin autophagy, GSK3β reduced expression
of Tnf
[92]
hesperidin oxidative stress (SOD, CAT,
MDA), tight junctions
restoration
of antioxidant pool
[93]
lycopene lipid peroxides, antioxidants reduced DNA damage [94]
Note. Results obtained in the experiments with preliminary or simultaneous administration of bioactive substances affecting
individual stages of the LPS/D-GalN-induced ALF pathogenesis highlight potential therapeutic targets. These targets are im-
plicated in three key pathogenic processes: hepatocyte death, activation of inflammatory signaling pathways (NF-κB, MAPK,
TLR4), and metabolic dysregulation (oxidative stress, glycolysis, autophagy).
alterations in hepatocyte metabolism, and production
of additional cytokines (Table 1).
Alongside genetically modified mouse strains, a
range of pharmacological agents is utilized to dis-
sect the pathogenic mechanisms of the LPS/D-GalN-
induced ALF and to explore novel therapeutic strate-
gies. These agents can be broadly divided into three
categories: inhibitors of cell death; modulators of
acute inflammatory responses (NF-κB, MAPK inhibi-
tors); and compounds that affect cell metabolism or
other aspects of pathogenesis (Table 2).
Several studies have demonstrated that prelimi-
nary oral administration of glucose (D-Glu) can pos-
itively affect survival of the wild-type mice in the
LPS/D-GalN-induced ALF model and in several oth-
er models [95, 96]. In the acetaminophen poisoning
model, the mechanism underlying this protective
effect involves the additional TLR4 activation signal
SYSONOV et al.1440
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
provided by the endogenous LPS, as mice lacking
TLR4 failed to acquire a protected phenotype [95].
Important evidence of the influence of hepatocyte
metabolism on the final outcome of the LPS/D-GalN-
induced ALF pathogenesis is the result obtained in
the mice with tissue-specific knockout of the Ninj1
gene in hepatocytes: such mice were resistant in this
model [75]. NINJ1 is a known inhibitory agent for
the xCT channel, which transports cystine, a precur-
sor of GSH, into the cell [76]. Further support for the
important contribution of xCT and ferroptosis to the
pathogenesis of LPS/D-GalN-induced ALF is provided
by the reduction in the levels of liver injury in mice
treated with alpinetin, an activator of the transcrip-
tion factor NRF2, which triggers synthesis of xCT and
serves as a key regulator of ferroptosis [84, 97].
Another group of agents that modulate the
pathogenesis of LPS/D-GalN-induced ALF are NF-κB
inhibitors. Their administration reduces the overall
pro-inflammatory background and contributes to the
lower liver damage [98]. Comprehensive understand-
ing of the potential molecular targets, influence on
which could change the nature and outcome of the
LPS/D-GalN-induced ALF (Table 2), enables the char-
acterization of a broader inflammatory landscape
involving a whole range of intercellular interactions
and molecular cascades.
The main cell populations involved in the known
part of the LPS/D-GalN-induced ALF pathogenesis are
immune cells, predominantly of myeloid origin, he-
patocytes, and intestinal epithelial cells – enterocytes.
Specific involvement of myeloid cells is indicated by
the role of TNF from this cellular source in the de-
velopment of lethal ALF [66]. It has been shown that
inhibition of TNF production by F4/80
+
cells results in
a completely protected phenotype in this model [89,
99]. Thus, it can be assumed that F4/80
+
myeloid cells
make the major contribution to the systemic produc-
tion of TNF that drives lethality. Hepatocytes, as spe-
cific targets of the D-GalN-dependent sensitization, are
directly susceptible to pro-inflammatory factors [40].
Enterocytes, may be damaged either by inflammatory
mediators accumulating in the peritoneal cavity or by
the direct action of LPS [100, 101].
INTESTINAL DAMAGE IN THE CONTEXT
OFMOUSE MODELS OFALF
The interaction between the intestine and the
liver represents a topic of considerable relevance
in the study of oncological diseases [102], metabol-
ic dysfunctions [103], and sepsis-dependent liver in-
jury [104]. For instance, it has been shown that the
resident liver macrophages are activated by neutro-
phils that have received a priming signal from the
intraepithelial lymphocytes (IELs) in the polymicrobi-
al inflammation model [105]. Intestinal damage and
the involvement of the intestine in the pathogenesis
of the inflammatory process are also observed in the
LPS/D-GalN-induced ALF [57].
However, due to the wide range of possible eti-
ologies of ALF, the data obtained from the individual
mouse models cannot be extrapolated to all clinical
cases. With careful interpretation of the research re-
sults, a number of aspects of ALF pathogenesis could
be identified that coincide in most etiologies. For
example, in the acetaminophen-induced ALF model,
rapid development of intestinal wall damage and
increased permeability was shown [106]. Elevated
blood endotoxin levels and impaired intestinal bar-
rier function are observed in the surgical models of
ischemia and partial liver resection, as well as in the
postoperative period in the clinical settings [107-109].
Collectively, the ALF models discussed and the avail-
able clinical data reveal a functional link between the
liver and the intestine during systemic ALF develop-
ment, a link that may offer promising avenues for
therapeutic intervention.
In addition to the inter-organ interactions, the
signals of chemotaxis of immune cells to the liver
during the ALF development, often determining se-
verity and rate of the disease progression, are the
subjects of the detailed studies and search for the
molecular mechanisms of regulation. Itisknown that
in the cases of acetaminophen poisoning with fatal
outcome, patients exhibit increased systemic produc-
tion of CXCL8, CCL2, and CXCL1– chemokines respon-
sible for recruitment of neutrophils and monocytes
[110]. The acetaminophen-dependent and LPS/D-GalN-
induced ALF models also demonstrate similar profiles
of chemokine production by hepatocytes [111, 112].
Particular attention in the study of LPS/D-GalN-
induced ALF has been devoted to the intestine. It has
been shown that in this model, the transcriptional
profile of enterocytes is altered: the expression of
genes associated with tight junctions decreases, while
the expression of pro-inflammatory genes and genes
linked to microbiota regulation increases, ultimately
leading to enhanced intestinal permeability [57]. The
effect of hesperidin aimed at improving intercellular
contacts of enterocytes (Table 2) leads to reduction
in the liver damage and transaminase levels in the
blood in the LPS/D-GalN-induced ALF model [93]. The
observed increase in the intestinal barrier permeabil-
ity during the LPS/D-GalN-induced ALF is associated
with the action of TNF, whose concentration signifi-
cantly increases 1.5-2 h after induction. TNF triggers
the degradation of the tight junction proteins, partic-
ularly ZO-1, claudin, and occludin, through a mecha-
nism mediated by activation of the MLCK and ROCK
kinases. According to the previously published study,
MOUSE MODELS OF HEPATOTOXICITY 1441
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
the TNF-induced disruption of intestinal barrier in-
tegrity depends on its interaction with TNFR2. In the
DSS-colitis model, the mice deficient in TNFR2 exhib-
ited less pronounced weight loss and disruption of
intestinal barrier permeability and exhibited greater
resistance to the development of colitis compared to
the control group. Meanwhile, no such phenotype
was observed in the TNFR1-KO mice, indicating a
potentially different contribution of TNF receptors to
the development of intestinal damage [113].
Thus, the intestine serves not only as a target
organ in ALF but also as an active site of pathogen-
esis, capable of influencing systemic inflammatory
response through the barrier function disruption,
production of pro-inflammatory signals, and modula-
tion of microbiota, thereby determining severity and
course of the disease. It is this active role of intestine
that goes beyond the classical understanding of ALF
as a local liver lesion and requires considering intes-
tine as a separate subject of discussion and justifies
interest in it as a potential therapeutic target, encom-
passing both the pharmacological protection of barri-
er function and the modulation of the gut microbiota.
CONCLUSION
Given the limitations of the above-discussed mod-
els, it should be emphasized that the evaluation and
comparison of multiple ALF models within a single
study may represent an important prerequisite for
obtaining reliable and clinically meaningful results.
The combination of immunogenic approaches with
hepatotoxins constitutes an in vivo ALF model that
yields a most closely resembling the manifestations
of the disease complicated by infection, a scenario
frequently observed in clinical practice [11, 12]. The
use of diverse immune system activators, including
induction of polymicrobial sepsis at one of the stag-
es of hepatotoxicity development, could be a more
relevant approach for modeling such complications
in classical ALF models [114]. In addition to existing
models with such combination, it could be interesting
to develop and investigate analogous models combin-
ing a pro-inflammatory antigen with another hepato-
toxin (LPS/APAP, LPS/CCl
4
, etc.).
Furthermore, considering the multifactorial na-
ture of ALF pathogenesis and involvement of intes-
tine in the disease progression, the identification of
molecular cascades linking intestinal permeability
with the severity of ALF could be promising for re-
ducing mortality in the patients in the acute phase
and reducing the risk of complications after liver
transplantation [115]. Forexample, it has been shown
that cecal resection in the TNF toxicity model pro-
tects mice from the lethal outcome by reducing the
overall level of damage-associated molecular patterns
(DAMPs) [116]. Thus, targeting the gut-liver axis and
associated DAMP-mediated inflammatory cascades
could be a promising direction for the development
of novel therapeutic approaches in ALF.
Another important direction for the advancement
of new therapeutic approaches lies in inhibition of
the key mediators of inflammation. Systemic blockade
of TNF, proposed in the early works by Beutler and
Cerami, has proven its effectiveness in the treatment
of arthritis and psoriasis [117-119]. Other agents of
this class are used to treat ulcerative colitis, Crohn’s
disease, and spondylitis. However, it is established
that the risk of developing central nervous system
inflammatory disorders is 37% higher in the patients
receiving anti-TNF therapy compared to the control
group [120]. Moreover, the patients on anti-TNF ther-
apy have an increased risk of tuberculosis infection
due to impaired formation and maintenance of gran-
ulomas [121, 122]. These observations collectively un-
derscore the necessity to inhibit TNF from a specific
cellular source rather than at the systemic level [123].
In the context of ALF, myeloid cells may constitute
such a source, blockade of TNF from these cells using
a bispecific antibody MYSTI has been shown to protect
mice from mortality in the experimental model [89].
Despite the variety of mouse models of ALF,
ranging from surgical (resection, ischemia) and phar-
macological (acetaminophen, CCl
4
, D-GalN) to immu-
nogenic (ConA, viral infections), none of them fully
reproduces complete clinical picture due to inter-
species differences in metabolism, immunity, and
pathogenesis dynamics. Combined models, in which
a pharmacological insult to the liver is potentiated
by an antigenic stimulus, such as LPS/D-GalN, most
closely approximate the clinical scenario. All of ALF
models described above require careful interpreta-
tion of the findings and repeated validation of the
observed parameters in several models to achieve
reliability and clinical significance. The adoption of
combined modeling approaches, together with the
investigation of inter-organ interactions, may unveil
new and promising therapeutic strategies.
In summary, in this review, we have identified
models that combine the action of a hepatotoxin and
an immune system activator to reproduce clinical
picture of the rapid development of ALF most close-
ly. An important direction for further study of ALF
pathogenesis is analysis of the involvement of intes-
tine in the early stages of the disease, as well as the
role of infectious complications, which arise in the
majority of clinical cases.
Abbreviations
ALF acute liver failure
D-GalN D-galactosamine
SYSONOV et al.1442
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
DAMPs damage-associated molecular
patterns
INR International Normalized Ratio
LPS lipopolysaccharide
TNF tumor necrosis factor
Supplementary information
The online version contains supplementary material
available at https://doi.org/10.1134/S000629792660239X.
Acknowledgments
The illustrations were prepared using the BioRender
graphic editor.
Contributions
S. A. Nedospasov and E. O. Gubernatorova – supervi-
sion of the work; F. A. Sysonov and K. E. Menshikov–
literature search, preparation of tables and figures;
F. A. Sysonov and E. A. Gorshkova – writing the text,
discussion; E. O. Gubernatorova, S. A. Nedospasov,
and M. S. Drutskaya – the text editing, conceptualiza-
tion of the study.
Funding
This work was financially supported by the Russian
Science Foundation (grant no. 26-15-00537).
Ethics approval and consent to participate
This work does not contain any studies involving hu-
man and animal subjects.
Conflict of interest
The authors of this work declare that they have no
conflicts of interest.
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