PARP‑1 in liver diseases: Molecular mechanisms, therapeutic potential and emerging clinical applications (Review)

Introduction

The liver has a strong regenerative capacity; however, chronic injury can lead to extracellular matrix accumulation, fibrosis and eventually liver failure, representing a major global health burden (1). In 2022, liver diseases such as cirrhosis, viral hepatitis and hepatocellular carcinoma (HCC) accounted for 2 million deaths worldwide (2). In China, the increasing prevalence of liver diseases highlights the requirement for more effective therapies (3). Conventional treatments offer limited efficacy in conditions such as non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD) and HCC (4–7). Therefore, it is important to identify shared molecular mechanisms to improve the diagnosis of liver diseases and identify more effective treatment strategies.

Poly(ADP-ribose) polymerase-1 (PARP-1), a key enzyme in the DNA damage response (DDR), also regulates cellular metabolism by modulating oxidized nicotinamide adenine dinucleotide (NAD+) levels and sirtuin 1 (SIRT1) activity (8–10). PARP-1 expression is upregulated in both primary and recurrent HCC and has been implicated in chemoresistance (11). The involvement of PARP-1 in the progression of various liver diseases, including non-alcoholic fatty liver disease (NAFLD), ALD and HCC, suggests its potential as a therapeutic target (12–14).

Unlike previous studies focusing on single disease types, the present review comprehensively analyzes the role of PARP-1 in multiple liver pathologies, including NASH, ALD, fibrosis and HCC, revealing shared molecular mechanisms. The dual role of PARP-1 in liver diseases is systematically summarized, and its functions in liver regeneration and pathological fibrosis are integrated to provide a comprehensive understanding of its regulatory mechanisms. In addition to summarizing established evidence, novel mechanistic insights into the regulation of tumor metabolism, transcriptional programming and immune microenvironment remodeling by PARP-1 in HCC are discussed, and the therapeutic synergy between PARP inhibitors and immune checkpoint blockade is highlighted. Furthermore, the translational potential of PARP-1 inhibitors for autoimmune liver diseases (AILDs) is proposed based on preclinical evidence, addressing a critical research gap. Overall, the present review synthesizes current knowledge on the expression, regulatory networks and mechanisms of PARP-1 in various liver diseases, ultimately evaluating its clinical diagnostic and therapeutic value.

Overview of liver disease

In 2022, liver disease resulted in 2 million fatalities worldwide, or 4% of total deaths globally, ranking it as the 11th largest cause of death (2). The main causes of mortality are complications arising from cirrhosis and HCC, while acute hepatitis accounts for a lower proportion of fatalities. The primary global causes of cirrhosis include viral hepatitis, alcohol use and NAFLD, which lead to a progressive deterioration of hepatic function. Other factors also contribute to liver disease, including age, sex, body composition, diet, physical activity, microbiome, and history of alcohol and tobacco use (15).

The liver performs essential biological tasks such as protein synthesis, glucose and lipid metabolism, detoxification and bile production. It exhibits marked immunological activity and functions as a systemic barrier against intestinal infections and toxins by maintaining a localized immune-regulating milieu and promoting tolerance to prevalent antigens (16). Optimal liver function is essential for the body to effectively combat bacteria and viruses; therefore, individuals with liver dysfunction are particularly susceptible to infections (17). The immune response generated by the liver relies upon its distinctive architecture, the presence of essential immune cells such as Kupffer cells (KCs), continuous immunological surveillance and rapid recruitment of immune cells (16,18). Chronic alcohol use increases the permeability of the gut to bacterial lipopolysaccharide (LPS) (19), elevates endotoxin levels in the hepatic portal vein, and activates KCs via interactions with Toll-like receptor-4 (14).

The liver has strong regenerative capacity and can recover considerably after resection. However, conditions such as ALD and chronic hepatitis B (CHB) may overly activate this regenerative response, resulting in the excessive accumulation of extracellular matrix and collagen, leading to liver fibrosis. Furthermore, decompensated liver fibrosis leads to the formation of hepatic scar tissue, which is known as cirrhosis. This significantly reduces liver function, and may progress to liver failure and death (1).

PARP-1, a DNA repair enzyme, plays a key role in hepatocyte apoptosis by promoting cell death and increasing the synthesis of pro-inflammatory mediators when overactivated by ROS and reactive nitrogen species, thereby influencing the self-healing capacity of the liver (10). NAFLD is a major contributor to chronic liver disease (CLD), with a spectrum ranging from moderate steatosis to advanced NASH. NASH is characterized by inflammation and progressive hepatocyte injury, which can lead to cirrhosis (20) and subsequently increase the risk of HCC.

Overview of PARP-1

PARPs are ADP-ribosyltransferases that catalyze ADP-ribosylation, a post-translational protein modification. ADP-ribosylation involves the cleavage of NAD+ to generate single ADP-ribose units, oligomers or polymers that are covalently linked to serine, glutamate, aspartate, arginine and lysine residues in target proteins (21). The PARP family comprises 17 proteins, with PARP-1 accounting for 85–90% of total PARP activity (22). PARP-1 contains several conserved and functionally distinct domains, including an auto-modification domain, a 55-kDa catalytic domain, and two zinc finger domains responsible for DNA binding (23).

PARP-1 is present in all human tissues, with the highest concentrations in the lymph nodes, appendix, brain, placenta, prostate, spleen and testes. It is an essential element in the DNA base excision repair mechanism (24,25) and participates in the repair of single-strand and double-strand breaks (DSBs) (26). Human PARPs, namely PARP-1, −2 and −3, are categorized as DDR proteins because of their involvement in DNA repair and reliance on DNA damage for activation (22). Among these, PARP-1 is the predominant enzyme, characterized by its abundance and strong enzymatic activity. It serves as the principal signaling factor in DDR, where its rapid activation is the most critical stage in the DDR process (8). PARP-1 serves as a primary sensor of DNA damage, capable of detecting DNA breaks within 3 sec of their occurrence, and triggers the recruitment of repair complexes via the ADP-ribosylation of proteins near the damage site. Its activity is further influenced by co-factors, such as histone PARylation factor 1 (HPF1), which enhances the catalytic activity of PARP-1 and modifies substrate selectivity. HPF1 interacts with the PARP-1 catalytic domain and colocalizes with it at sites of DNA damage (8).

A study evaluating the hepatotoxicity of columbin (CLB) demonstrated that CLB induces DNA damage both in vitro and in vivo, which is associated with the upregulation of PARP-1 (27). PARP-1 also interacts with SIRTs. SIRT1-7 are a family of NAD+-dependent protein deacetylases with extensive roles in metabolism and aging. In the absence of PARP-1, NAD+ levels rise, potentially increasing SIRT1 activity (22,28). In addition, PARP-1 and AMP-activated protein kinase (AMPK) mutually reinforce each other: The activation of PARP-1 stimulates AMPK, which in turn phosphorylates and activates PARP-1. Within the reactive oxygen species (ROS)-PARP-1-AMPK pathway, the interaction between PARP-1 and AMPK promotes the nuclear export of AMPK, which induces autophagic flux and cellular apoptosis (22,29).

PARP-1 plays an essential role in DNA repair and cellular stress responses in the liver. During oxidative stress, such as exposure to hydrogen peroxide, PARP-1 activation preserves hepatocyte survival, while PARP-1 inhibition or genetic ablation in primary hepatocytes diminishes oxidation-induced necrotic cell death, suggesting a preventive mechanism against oxidative injury (10).

A pilot study revealed that PARP-1 knockout mice exhibit impaired liver regeneration and reduced hepatocyte proliferation. It also showed that PARP-1 is required for both the early liver response and late tissue repair during liver regeneration, and that PARP-1 inhibitors can reduce hepatocyte proliferation (30). These results indicate that PARP-1 and its catalytic activity are essential for hepatocyte proliferation. This effect appears to be associated with Yes-associated protein (YAP), a key driver of hepatocyte proliferation (31). In PARP-1 knockout mice, YAP activity and the expression of cell cycle-related proteins in liver tissue are suppressed, resulting in reduced hepatocyte proliferation and impaired liver repair during liver regeneration (30). However, another study showed that chronic or excessive activation, such as that observed in severe or long-standing liver disease, depletes NAD+ and promotes fibrosis, ultimately impairing liver regeneration (32). In view of this duality, the inhibition of pathological activation while retaining the beneficial functions of PARP-1 is a therapeutic challenge.

Chromatin relaxation is essential for efficient DNA repair, and PARP-1 functions as a crucial mediator of this process. The inhibition of PARP-1 activity directly affects chromatin structure. Through poly(ADP-ribosyl)ation, PARP-1 binds to and modifies chromatin remodelers, thereby altering chromatin structure and facilitating the ensuing DDR (33).

PARP-1 also plays a pivotal role in inflammation. It activates nuclear factor κB (NF-κB), nuclear factor of activated T cells and activator protein 1, leading to the production of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, and effector T cell cytokines, including IL-4 and IL-5. Excessive activation of PARP-1 promotes cell death and tissue damage, thereby exacerbating the inflammatory response (34). These functions are particularly relevant to chronic inflammatory liver conditions, including viral hepatitis, ALD and drug-induced liver injury (DILI).

PARP-1 is essential for sustaining proper immune function, and its dysregulation contributes to immune-mediated disorders. Under physiological conditions, PARP-1 expression is typically low but becomes significantly upregulated during early liver injury, chronic liver fibrosis and HCC (10). Consequently, aberrant PARP-1 activity is associated with the progression of several liver disorders.

Function of PARP-1 in liver disease

Hepatitis

Viral hepatitis

Viral infection is a major cause of acute hepatitis, which leads to elevated liver transaminase levels and impaired liver function (35). China is among the top 20 nations with the highest viral hepatitis burdens. Between 2016 and 2022, the proportion of people living with viral hepatitis confirmed hepatitis B cases in China increased from 19 to 24%, while that of hepatitis C cases increased from 22 to 33% (36). CHB infection is the major cause of HCC. Transforming viral proteins such as hepatitis B virus (HBV) regulatory protein X (HBx) are key oncogenic factors (37). HBx induces the degradation of the structural maintenance of chromosome 5/6 complex, a process implicated in HBV-related HCC. This impairs homologous recombination (HR)-mediated DNA repair, thereby contributing to carcinogenesis. The accumulation of double-stranded DNA (dsDNA) breaks in cancer cells with HR deficit (HRD) can be lethal. PARP-1 inhibition prevents the repair of single-strand DNA breaks, which subsequently exacerbates the accumulation of dsDNA breaks (38,39). In addition to altering protein function, HBV infection regulates the expression of certain long non-coding RNAs (lncRNAs) in infected cells. For example, HBx inhibits p53 activity, leading to the upregulation of lncRNA-HUR1 expression, which promotes cell proliferation and cancer progression (40). The overexpression of lncRNA-HUR1 reduces caspase-3/7 activity and PARP-1 cleavage, while lncRNA-HUR1 knockdown increases caspase-3/7 activity and promotes PARP-1 cleavage (41). Together, these findings underscore the crucial role of PARP-1 in HBV-induced HCC.

In addition to HBV, other viral hepatitis subtypes may also interact with DNA damage and repair pathways. Although PARP-1 has not been extensively studied in these contexts, existing data suggest a potential involvement that is worthy of further exploration. Hepatitis C virus (HCV) is a leading cause of CLD and HCC that induces persistent oxidative stress and DNA damage in infected hepatocytes. Viral proteins, including core protein and the non-structural (NS) proteins NS3 and NS5A disrupt host DNA repair pathways by targeting key components, such as the ataxia telangiectasia-mutated (ATM)-nibrin-meiotic recombination 11 complex, thereby promoting chromosomal instability and malignant transformation (42,43). Although direct studies of PARP-1 in HCV-infected liver tissue are limited, the well-established roles of this enzyme in DDR and inflammation suggest that PARP-1 may be activated under conditions of HCV-induced genomic stress, potentially contributing to fibrosis and cancer progression. Hepatitis D virus (HDV), which often co-occurs with HBV, is associated with more severe disease and heightened oxidative stress (44), factors that may also induce PARP-1 activation. However, direct evidence associating PARP-1 with HDV-induced liver injury is lacking.

Collectively, these observations highlight the importance of investigating the role of PARP-1 in diverse forms of viral hepatitis, as its regulatory role in DNA repair, cell death and the inflammatory response may have major implications for the diagnosis and treatment of various liver infections.

ALD

Liver damage, inflammation, fibrosis, cirrhosis and cancer resulting from prolonged or excessive alcohol consumption are hallmarks of ALD. With 3.3 million associated fatalities, or 6% of all deaths globally, alcohol-related damage is one of the most prevalent preventable causes of mortality. Liver damage occurs in 20–30% of individuals who misuse alcohol (45). A key pathogenic characteristic of ALD is hepatocyte apoptosis mediated by PARP-1. Under normal physiological conditions, alcohol dehydrogenase is the primary enzyme that metabolizes ethanol in the liver. However, chronic alcohol intake stimulates the expression of cytochrome P450 2E1, which metabolizes ethanol to acetaldehyde and produces considerable amounts of ROS as byproducts (46). Acetaldehyde is a toxic metabolite that forms adducts with cellular macromolecules and further amplifies oxidative stress. ROS can induce oxidative DNA damage, which is sensed by PARP-1 and activates the TGF-β1-Smad pathway. In the early stages of DNA damage, PARP-1 binds to sites of DNA damage and uses NAD+ as a substrate to synthesize PARPs including PARP-1 (47). However, persistent or severe DNA damage leads to the overactivation of PARP-1, which consumes large amounts of NAD+ for poly(ADP-ribosyl)ation, leading to NAD+ and ATP depletion along with impaired mitochondrial function and energy metabolism, ultimately triggering hepatocyte necrosis or monocytic cell death (48,49).

Preventing and treating ALD requires the reversal of this imbalance caused by PARP-1 overactivation that leads to hepatocyte necrosis or monocyte death (50). In ALD, hepatocytes and liver macrophages exhibit upregulated C-C chemokine ligand type 2 (CCL2) levels. A pharmacological study of mice revealed that alcohol-induced liver damage can be prevented or reversed by blocking the activation of C-C chemokine receptor type 2 and 5 (51). Alcohol-induced increases in PARP-1 activity have also been shown to mediate hepatocyte apoptosis (14,52). In Raw264.7 macrophages, PARP-1 activation promotes the nuclear translocation of LPS-induced NF-kB, and increased KC activation exacerbates alcohol-induced liver steatosis by increasing hepatic M1 macrophage marker gene expression. Consistent with this, treatment of mice with the PARP-1 inhibitor PJ34 downregulates hepatic M1 marker gene expression (14). This suggests that limiting KC activation helps to restore hepatic lipid balance, an important protective mechanism of PARP-1 inhibition in alcohol-induced hepatic steatosis. Certain medications, such as cenicriviroc, have been demonstrated to reduce hepatocyte apoptosis and alleviate CCL2-induced hepatic steatosis (52).

NAFLD

Based on histological features, NAFLD can be classified as NASH, which comprises <20% of cases, and non-alcoholic fatty liver (NAFL), which comprises the remaining >80% (53,54). NAFL is defined as hepatic steatosis without substantial hepatocyte injury, or minor lobular inflammation is present, while NASH is characterized by hepatocyte damage in addition to steatosis (54). With an estimated global incidence of 25%, NAFLD is a growing public health concern. In the United States, severe NASH is now the second most frequent indication for liver transplantation in men and the most common indication in women (55). Nearly 75% of individuals in the United States with risk factors such as diabetes and obesity develop NAFLD (56).

In early NAFLD, the gut vascular barrier is disrupted, which allows intestinal bacteria to proliferate, leading to increased translocation of LPS to the liver, thereby triggering pyroptosis. LPS stimulation also activates PARP-1, which increases signaling via NF-κB, a crucial transcription factor that regulates the production of pro-inflammatory cytokines. Specifically, PARP-1 interacts with transcription factors and co-activators, including p300, to increase the transcriptional activity of NF-κB. This then influences the expression of cytokines and other pro-inflammatory mediators, including inducible nitric oxide synthase and cyclooxygenase-2, thereby contributing to the inflammatory response in hepatic tissue (34). In high-fat diet (HFD)-induced mouse models, DNA damage activates PARP-1, which stimulates the activation of NLR family pyrin domain containing 3 (NLRP3) and its downstream signaling proteins (57). This is associated with increased levels of cleaved PARP-1 together with elevated blood levels of IL-1β and C-reactive protein (58). Beyond inflammation, the development of NAFLD is strongly influenced by the SIRT1/AMPK pathway and NAD+ homeostasis. PARP-1 contributes to this dysregulation by depleting NAD+ and interfering with SIRT1 activity, which is essential for AMPK activation (59). SIRT1 modulates hepatic lipid metabolism by regulating the activity of peroxisome proliferator-activated receptors (PPARs) (60). PARP-1 activity also disrupts hepatic lipid homeostasis by modulating the SIRT1/PPARα axis. It depletes intracellular NAD+, directly poly(ADP-ribosyl)ates PPARα, and impairs both SIRT1 activity and the PPARα-mediated transcription of β-oxidation genes, leading to suppressed mitochondrial function and fatty acid oxidation (61,62). This promotes lipid accumulation and the progression of steatosis. By contrast, the activation of SIRT1 enhances hepatic lipid catabolism and mitochondrial efficiency, serving as a critical counterbalance in the maintenance of metabolic adaptation during NAFLD progression (63). Collectively, these insights highlight the pivotal regulatory function of the PARP-1/SIRT1/PPARα axis in the pathophysiology of NAFLD.

DILI

Unanticipated liver damage caused by drugs or other xenobiotics, known as DILI, is a major concern in clinical trials and drug development (64). A wide range of agents, including medications, natural products and supplements, can cause DILI (65). DILI is challenging to diagnose, requires the rigorous elimination of other causes, and is underreported to pharmacovigilance authorities; therefore, its prevalence is challenging to determine (66,67). While traditional and nutritional supplements are the primary causes of DILI in Asia, drug responses to conventional pharmaceuticals are most prevalent in the United States and Europe (67). With an estimated 23.8 cases per 100,000 individuals, the frequency of DILI is high in China (68). However, the actual incidence could be much higher than this.

The mechanisms underlying liver injury vary depending on the causative agents. Experimental models hased on DILI principles have been developed to assess the efficacy of liver protective and anti-fibrosis interventions. For example, carbon tetrachloride can induce liver fibrosis and injury, processes that are often accompanied by DNA damage and repair processes, with PARP-1 playing a key role in the DDR (49). The overactivation of PARP-1 promotes the binding of transcription factor activator protein 1 to the TGF-β1 gene, leading to chronic chemical damage in human and animal liver cells (69). Another example of a liver injury-inducing agent is CLB, which increases ROS production and depletes glutathione. The resulting oxidative stress promotes DNA breaks and upregulates PARP-1 expression (27).

PARP-1 is activated during acetaminophen overdose, resulting in poly(ADP-ribosyl)ation of the pregnane X receptor. This post-translational modification augments the transcription of the cytochrome P450, family 3, subfamily A, polypeptide 11 enzyme, thereby increasing the production of toxic acetaminophen metabolites (70). Furthermore, anti-tuberculosis medications, including isoniazid and rifampicin, can induce marked hepatic damage by inducing an inflammatory response and oxidative stress, subsequently activating the NLRP3 inflammasome. This induces PARP-1 activation, which contributes to hepatic damage (71).

AILD

There are three principal types of AILD, a chronic immune-mediated illness that affects hepatic and bile duct cells, which are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) (72,73). A clinical phenotype known as overlap syndrome occurs when symptoms of multiple categories co-exist within the spectrum of AILD; however, the majority of patients fit the criteria of one specific type (74). AILD has a male-to-female ratio of 1:5, and an annual yearly incidence worldwide of 1.37 cases per 100,000 individuals. PBC mostly affects women, and has a prevalence of 39.2 per 100,000 in the United States and 4.75 per 100,000 in Korea (75).

Studies have shown that the pathophysiology of autoimmune disorders is associated with increased PARP-1 activation (76,77). Trichloroethene exposure induces autoimmune reactions, leading to increased apoptosis, immune activation and the upregulation of PARP-1 expression following the development of anti-single-stranded DNA antibodies (78). Concanavalin A (ConA) causes liver damage via a mechanism comparable to the clinical alterations and immunological responses observed in patients with AIH (79). In AIH model mice, the liver exhibits widespread necrosis, marked macrophage infiltration, and elevated levels of the pro-inflammatory cytokine TNF-α (80). Following ConA induction, PARP-1 levels and TNF-α production increase, which contributes to PARP-1 activation (80).

Although PARP-1 has been implicated in the regulation of inflammation and T cell-mediated immune responses, direct evidence for the use of PARP inhibitors in animal models of AILD, including AIH, PBC and PSC, is currently lacking. The ConA-induced hepatitis model has been widely employed to investigate the immunopathogenesis of AIH, owing to its ability to simulate CD4+ T cell-mediated hepatic injury (81). Notably, genetic ablation of PARP-2, but not PARP-1, confers significant protection against ConA-induced liver damage, suggesting isoform-specific roles of PARP enzymes in immune liver injury (82). However, the role of PARP-1 remains incompletely understood in this context. Given the established involvement of PARP-1 in the amplification of NF-κB-mediated proinflammatory cytokine release and the modulation of CD4+ T cell polarization (83), it is plausible that PARP-1 inhibition may mitigate immune-driven hepatic inflammation in AIH (84). Accordingly, future studies utilizing pharmacological PARP-1 inhibitors such as PJ34 or olaparib, or gene-silencing approaches in AIH models, such as the ConA-induced hepatitis model, are warranted to determine whether PARP-1 is a viable therapeutic target in AILD.

Liver fibrosis

Persistent liver injury, such as hepatitis, can lead to liver fibrosis. This condition is characterized by the buildup of extracellular matrix proteins, primarily cross-linked type I and III collagen, which replace damaged normal tissue following cholestatic and hepatotoxic injury. The resulting fibrous scarring impairs the structural integrity of the liver tissue and disrupts the homeostatic function of hepatocytes (85). Liver fibrosis may eventually develop into cirrhosis, which is associated with high morbidity and mortality, and increases the risk of HCC and chronic liver failure (86).

Hepatic stellate cells (HSCs) are non-parenchymal cells located in the subendothelial region of the liver and are the major mediators of liver fibrosis. A promising strategy to mitigate the development of liver fibrosis is the induction of senescence in activated HSCs (87). HSC apoptosis can be accurately predicted based on changes in PARP-1 levels (88). Studies have shown that autophagy exacerbates liver fibrosis by breaking down lipid droplets in HSCs, thereby activating the HSCs. Conversely, the suppression of autophagy promotes HSC death and reduces proliferation. Elevated levels of cleaved PARP are associated with HSC apoptosis, which can be induced by pharmacological agents such as berberine (BBR) and carvedilol (89,90). Specifically, BBR blocks autophagy in HSCs and downregulates autophagy protein 5 expression, which leads to HSC death (90). In addition, PARP-1 activation is associated with increased TGF-β expression. In activated KCs, upregulated PARP-1 expression promotes TGF-β production, further stimulating HSC activation (10).

HCC

Liver cancer ranks fourth in cancer-related mortality and is the sixth most prevalent cancer worldwide, with HCC accounting for >80% of cases (91,92). With a yearly incidence rate of 1–6%, cirrhosis of any etiology is the biggest risk factor for HCC. Indeed, HCC is the primary cause of mortality in individuals with cirrhosis (93). Compared with nearby normal tissues, HCC exhibits numerous chromosomal aberrations and elevated PARP expression, which accumulates during DNA replication (94,95). PARP-1 inhibition has been suggested to be an effective treatment for HCC, particularly in BRCA-deficient tumors (94).

Emerging evidence indicates that PARP-1 enhances glycolysis and metabolic reprogramming in tumor cells by physically interacting with hypoxia inducible factor-1α, stabilizing it, and acting as a transcriptional coactivator (96). This promotes the expression of hexokinase 2 and other glycolytic enzymes, thereby reinforcing the Warburg effect in HCC and facilitating tumor proliferation (97). Beyond its role in DNA repair, PARP-1 also functions as a transcriptional coregulator, interacting with NF-κB and STAT5 to facilitate the expression of pro-inflammatory and tumorigenic genes (98), which promotes chronic inflammation, cell proliferation and angiogenesis in HCC. PARP-1 also modulates the tumor immune microenvironment through multiple mechanisms. PARP inhibition leads to the accumulation of cytosolic DNA, activation of the cyclic GMP-AMP synthase-stimulator of IFN genes-type I IFN pathway and upregulation of programmed death ligand-1 (PD-L1), thereby reshaping immune cell infiltration and enhancing antitumor immunity (99). A preclinical study of HCC demonstrated that olaparib upregulates PD-L1 via the suppression of microRNA-513, and its combination with anti-programmed cell death protein-1 (PD-1) therapy significantly enhances CD8+T-cell infiltration and antitumor efficacy (100). Broader oncology studies indicate that PARP inhibitor plus immune checkpoint inhibitor combinations are well-tolerated and exhibit synergistic antitumor effects, which justifies their translational exploration in HCC (101–103).

Caspase-3 is an effector protein in cancer cell apoptosis, which promotes apoptosis by cleaving PARP-1 (104). Notably, HCC progression is associated with decreased levels of both PARP-1 and cleaved caspase-3. DNA damage repair fails when PARP-1 is cleaved, as the cleaved form of PARP-1 can no longer repair DNA (104–106). Peptides derived from Laminaria japonica promote apoptosis by increasing cleaved caspase-9 and caspase-3 levels and activating PARP, potentially through upstream apoptotic signal-regulating kinase 1 (ASK1) phosphorylation and subsequent p38 MAPK activation (107). Factors upstream of PARP-1, such as JNK1/2 and ERK1/2, may also regulate cell death following PARP-1 inhibition (108). This mechanism can kill cancer cells and provides a potential therapeutic avenue for HCC. However, the upregulation of MET expression in HCC presents a challenge: Oxidative DNA damage activates MET, which interacts with and phosphorylates PARP-1 at tyrosine 907, thereby limiting the effectiveness of PARP-1 inhibitors in HCC (109). Future studies on the use of PARP inhibitors for the treatment HCC should account for this mechanism.

A summary of the targets and associated molecules or complexes of PARP-1 in liver diseases is presented in Table I.

Table I. Targets, associated molecules and complexes of poly(ADP-ribose) polymerase-1 in liver diseases.

Table I.

Targets, associated molecules and complexes of poly(ADP-ribose) polymerase-1 in liver diseases.

First author/s, year	Liver disease type	Target, associated molecule or complex	(Refs.)
Mukhopadhyay et al, 2014	Liver fibrosis	TGF-β	(10)
Zhang et al, 2016	ALD	NF-κB	(14)
Liu et al, 2018	Viral hepatitis	lncRNA-HUR1	(40)
Yin et al, 2022	ALD	C-C chemokine ligand type 2	(51)
Ye et al, 2022	NAFLD	NLRP3	(57)
Salomone et al, 2017	NAFLD	SIRT1, AMPK	(60)
Gallyas and Sumegi, 2020	Drug-induced liver injury	Activator protein 1, TGF-β1	(69)
Liu et al, 2023	Autoimmune liver disease	TNF-α	(80)
Ishteyaque et al, 2024	Hepatocellular carcinoma	Caspase-3	(104)

[i] ALD, alcoholic liver disease; AMPK, AMP-activated protein kinase; lnc, long non-coding; NAFLD, non-alcoholic fatty liver disease; NF-κB, nuclear factor κB; NLRP3, NLR family pyrin domain containing 3; SIRT1, sirtuin 1; TNF-α, tumor necrosis factor-α.

PARP-1-mediated cellular signaling pathways in liver disease

The onset and progression of liver diseases involve intricate molecular pathways that are poorly understood and associated with a poor prognosis. PARP-1 activity is both directly or indirectly regulated by a variety of signals, rendering it a potentially useful biomarker for detecting the onset of liver disorders and monitoring their course. This section summarizes the key cellular signaling pathways in which PARP-1 participates and their contributions to the pathogenesis of various liver disorders.

The regulation of tumor cell growth and death is strongly influenced by lncRNAs. Numerous lncRNAs that promote the proliferation of tumor cells also decrease their apoptosis (110). For example, Chen et al (41) reported that lncRNA-HUR1 increases Bcl-2 expression and reduces Bax expression by suppressing p53 activity. This inhibits caspase-3/7 activation via the intrinsic apoptosis pathway, thereby preventing PARP-1 cleavage and cell death. Conversely, the study demonstrated that in cell lines with stable lncRNA-HUR1 knockdown, Bcl-2 expression is reduced, Bax expression is increased and caspase-3/7 activation is promoted, which in turn accelerates PARP-1 cleavage and cell death (41). Although few lncRNAs have been thoroughly investigated in the context HCC, lncRNAs in general have been demonstrated to be essential for the development and progression of HCC (111), indicating their potential as both diagnostic and therapeutic targets (Fig. 1).

Figure 1. lncRNA-HUR1 suppresses the intrinsic apoptosis pathway by inhibiting PARP-1 cleavage, leading to HCC cell proliferation. HCC, hepatocellular carcinoma; lnc, long non-coding; PARP-1, poly(ADP-ribose) polymerase-1.

PARP-1 can sense DNA damage and trigger the TGF-β1-Smad signaling pathway. TGF-β1 is produced by endothelial, hematopoietic and connective tissue cells, and has been associated with heart failure in several studies (49,112,113). A main cause of hepatic fibrosis (HF) is the activation of HSCs. When DNA damage occurs, PARP-1 is recruited and activates TGF-β1-Smad pathway by upregulating TNF-α in HSCs, which increases ASK1-JNK phosphorylation. This exacerbates HF by promoting epithelial-to-mesenchymal transition and the deposition of α-smooth muscle actin (α-SMA) and collagen I/III. Dihydrokaempferol has been shown to decrease TNF-α transcription and inhibit the PARP-1-regulated TGF-β1 pathway, thereby reducing the levels of phosphorylated (p-)Smad 2/3 and p-ERK 1/2 (MAPK1). This is associated with suppression of the ability of HSCs to produce α-SMA and collagen I/III, contributing to the mitigation of HF, potentially by inhibition of the downstream NF-κB and ASK1-JNK signaling pathways (49) (Fig. 2).

Figure 2. Main molecular targets regulated by PARP-1 in HF. PARP-1 detects damaged cellular DNA and initiates the ASK1-JNK pathway, leading to EMT and increased collagen I/III and α-SMA expression, which exacerbates HF. α-SMA, α-smooth muscle actin; ASK1, apoptotic signal-regulating kinase 1; EMT, epithelial-to-mesenchymal transition; HF, hepatic fibrosis; HSCs, hepatic stellate cells; KCs, Kupffer cells; PARP-1, poly(ADP-ribose) polymerase-1.

SIRT1 is an NAD+-dependent deacetylase that plays a key role in the regulation of PPARα activity. Its expression and activity are regulated by NAD+, which serves as its substrate (114,115). Consequently, intracellular NAD+ levels can directly influence PPARα signaling. In the liver, PPARα signaling is markedly inhibited in the absence of SIRT1. The inhibition of PARP-1 can raise intracellular NAD+ levels, thereby increasing SIRT1 activity, and upregulating PPARα signaling and mitochondrial oxidation. The PARP-1-mediated poly(ADP-ribosyl)ation of PPARα suppresses its transcriptional activity by preventing PPARα from binding to SIRT1 and from recruiting the PPARα/SIRT1/PPARg coactivator-1α complex to target promoters (115). Notably, the liver PARP activity of patients with severe NAFLD is much greater than that of patients with simple steatosis, suggesting that aberrant PARP-1 activation may contribute to the downregulation of liver PPARα expression in these individuals (115). These findings suggest that inhibition of PARP-1 may have therapeutic potential in the prevention and treatment of NAFLD (Fig. 3).

Figure 3. PARP-1 suppresses transcription by preventing PPARα from recruiting the PPARα/SIRT1/PGC-1α complex to target promoters. This may have specific implications in the prevention and treatment of NAFLD when PARP-1 activity is inhibited. NAD+, oxidized nicotinamide adenine dinucleotide; NAFLD, non-alcoholic fatty liver disease; PARP-1, poly(ADP-ribose) polymerase-1; PGC-1α, PPARγ coactivator-1α; PPARα, peroxisome proliferator-activated receptor α; SIRT1, sirtuin 1.

The accumulation of β-catenin has been observed in a mouse model of liver cancer (116). Valanejad et al (117) identified a subset of 250-bp human chromosomal domains, known as aggressive liver cancer domains (ALCDs), that are located close to genes associated with various cancer pathways and are regulated by PARP-1. Hepatoblastoma (HBL) is a type of pediatric liver cancer that primarily affects children <3 years old (118). Notably, the PARP-1-ALCD axis modulates β-catenin, a potent promoter of aggressive liver cancer, which is markedly increased in aggressive HBL (117). PARP-1 activation can contribute to the development of HBL by activating the Wnt/β-catenin pathway and inducing post-translational changes in tumor suppressor genes. Conversely, PARP-1 inhibition can decrease cell proliferation, block Wnt/β-catenin signaling, and restore the expression of tumor suppressor genes (119). These findings suggest that targeting proteins associated with the Wnt/β-catenin pathway may represent a potential therapeutic approach for liver cancer.

The PI3K/Akt/mTOR signaling pathway inhibits apoptosis while enhancing cell survival and proliferation, and is associated with angiogenesis, carcinogenesis, invasion, and metastasis in several cancers, including colorectal cancer and non-small cell lung cancer (120,121). Numerous studies have examined the effects of natural substances on HCC, some of which target this pathway. For example, in one study, the treatment of HepG2 cells with 13-acetoxysarcocrassolide reduced p-PI3K, p-AKT and p-mTOR levels, indicating suppression of the PI3K/Akt/mTOR signaling pathway. This inhibition decreased the mTOR-mediated phosphorylation of p70S6K and its downstream effectors S6 and eukaryotic translation initiation factor 4B, and also increased cleaved PARP-1 levels, indicating that the induced apoptosis was facilitated by mitochondrial dysfunction. These findings suggest that PARP-1 activity may be associated with the phosphorylation of AKT, which influences downstream mTOR signaling and promotes tumor cell proliferation and apoptotic resistance (122).

Mechanistically, PARP-1 further promotes HCC growth by forming a positive feedback loop with the PI3K/AKT/mTOR signaling axis. PARP-1 activation increases the phosphorylation of AKT at serine 473, which activates mTOR complex 1 (mTORC1) targets such as ribosomal protein S6 kinase 1 and eukaroytic translation initiator factor 4E binding protein 1, thereby driving protein synthesis, cell proliferation and survival while inhibiting apoptosis (123–125). Conversely, PARP-1 inhibition downregulates AKT activity via upregulation of PH domain leucine-rich repeat protein phosphatase 1, highlighting the direct role of PARP-1 in the modulation of AKT/mTOR signaling (126). The activation of AKT/mTOR signaling has been demonstrated to support the stability and activity of PARP-1, with PARP-1 activation modulating mTORC1 through AMPK-dependent mechanisms, and AKT activation enhancing DDR components, including PARP-1 itself (124,127). This mutual reinforcement establishes a negative feedback loop of pro-survival signaling and genomic maintenance that promotes HCC progression and therapy resistance. Preclinical studies indicate that disrupting either PARP-1 or the PI3K/AKT/mTOR pathway can disrupt this feedback loop, reduce tumor viability, and sensitize cells to treatment (125,126,128).

These findings indicate that PARP-1 regulates several cellular signaling pathways and is crucial for the onset, progression and clinical signs of several liver diseases. This suggests the potential of PARP-1 as a prognostic indicator and possible target for liver disease therapy.

Potential clinical value of PARP-1 in liver disease

In emerging nations, particularly in the Asia-Pacific region, liver diseases are becoming widely acknowledged as major health concerns. While viral hepatitis remains the primary cause of morbidity and death, ALD and NAFLD are contributing to the liver disease burden at an accelerating rate (129).

PARP-1 expression in upregulated in numerous cancers, and prompt evaluation of its expression is important when devising a treatment plan and monitoring therapeutic effectiveness. Positron emission tomography (PET) imaging is an efficient, noninvasive, real-time technique that can be used to assess PARP-1 activity throughout the body. In 2016, researchers conducted preclinical evaluations and the first-in-human study of PARP activity in cancer. Notably, the study observed increased uptake of 18F fluorthanatrace (18F-FTT) in a patient with HCC (130). However, investigations of PARP-targeted imaging in liver diseases, including NASH, ALD and HCC, remain at the preclinical stage (131), including a study of PARP-targeted PET imaging in NASH animal models (132). Clinical trials of PARP-1 PET probes such as 18F-FTT have so far been limited to other tumor types, including breast, ovarian and prostate cancer (133), with no direct applications in liver pathology. This highlights a critical gap and opportunity for the future clinical translation of PARP-1 in liver diseases.

A number of tracers targeting PARP-1 have been developed, including 18F-FTT and the olaparib analog 18F-PARPi. Patients with elevated PARP-1 expression can be identified by PET imaging using 18F-FTT (134). A recent study designed a high-affinity PARP-1 molecule, 18F-BIBD-300, by chemical modification of the main pharmacophore of 18F-FTT. Since 18F-FTT has been used to diagnose liver cancer,18F-BIBD-300 has been suggested to have potential for this purpose (135). 18F-PARPi and 18F-FTT both undergo hepatobiliary clearance, which may limit their effectiveness in the imaging of abdominal lesions, such as liver metastases (136). 18F-FPyPARP, a 6-fluoronicotinoyl analog of 18F-PARPi, has been found to be an excellent radioactive tracer for PARP expression that is simpler to manufacture and less lipophilic than 18F-PARPi (136).

PARP inhibitors have emerged as leading cancer treatments for BRCA-deficient patients with ovarian and breast cancers (137). Notably, although all PARP-1 drugs are classified as PARP inhibitors, not all PARP inhibitors are selective for PARP-1. Thus, PARP-1 inhibitors constitute a distinct subgroup within the broader category of PARP inhibitors. The clinical utility of PARP inhibitors may be attributed to their ability to efficiently kill cells with HRD in BRCA1/2-deficient cancers by driving the accumulation of unrepaired DNA damage and inducing synthetic lethality (138).

Common adverse reactions reported in cancer trials of various PARP inhibitors, including olaparib and niraparib, include anemia, leukopenia, thrombocytopenia, nausea, vomiting and fatigue (139,140). While these adverse reactions have been observed in patients with cancer, patients with liver disease often have cytopenias, such as thrombocytopenia due to cirrhosis (141); therefore, PARP inhibitors may exacerbate hematological complications that are already present. Nausea and vomiting are also common symptoms of PARP inhibitors, occurring in >20% of patients, which may exacerbate malnutrition in patients with advanced liver disease (142). In addition, niraparib has been associated with nephrotoxicity; impaired hepatic albumin synthesis, such as that occurring in cirrhosis, may increase free drug concentrations, thereby exacerbating nephrotoxicity (143,144).

Evidence for the efficacy of PARP-1 inhibitors in liver diseases, including NAFLD/NASH, ALD, liver fibrosis/cirrhosis and HCC, comes primarily from cell and animal models. For example, one study demonstrated that PARP-1 inhibition contributed to the antifibrotic effect of puerarin in mice (145), suggesting that targeting PARP-1 has therapeutic potential for liver fibrosis. Another study used mouse models of NASH to verify that PARP inhibition and PARP-1 deletion reduce hepatic triglyceride accumulation, metabolic disorders, inflammation and/or fibrosis (146), indicating that PARP inhibition may be a promising treatment strategy for fatty hepatitis. Limited data from patients are also available: A pilot study using liver samples from patients with NAFLD confirmed that PARP-1 is activated in human fatty liver, as well as in a HFD-induced mouse model (61). In addition, a study at the University of Minnesota analyzed liver tissue samples from patients with alcoholic and HBV-related cirrhosis (stage 3–4 fibrosis). The results of the study demonstrated the key pathogenic role of PARP-1 in liver fibrosis and the potential of PARP-1 inhibitors to restore liver function after fibrosis (10). Collectively, these studies suggest that repurposing PARP-1 inhibitors to treat liver diseases associated with injury, inflammation and fibrosis may have potential clinical applicability.

PARP-1 inhibitor monotherapy appears to be largely ineffective in HCC, likely due to the BRCA nature of this cancer type. However, one study investigated non-BRCA1/2 gene abnormalities, and found that they confer sensitivities to PARP inhibition comparable to those observed with BRCA1/2 mutations (147). In addition, marked suppression of HCC cell growth was observed both in vitro and in vivo following treatment with a combination of wild-type p53-induced protein phosphatase 1 and PARP inhibitors (138). Synergistic strategies comprising PARP inhibitors and radiotherapy have also been shown to improve HCC management, with olaparib increasing the radiosensitivity of HCC cells by promoting extensive DSBs (148). In addition, dual inhibition of PARP-1/2 and tankyrase 1/2 exhibited potent anticancer activity with strong synergy, suggesting an expanded therapeutic scope for PARP-1 inhibitors (149).

Likewise, both ALD and NAFLD may be prevented by blocking PARP-1. Since NAD+ plays a crucial role in acute alcoholic liver injury, preserving NAD+ levels by blocking PARP may help to maintain liver homeostasis (12). In addition, the pharmacological inhibition or genetic deletion of PARP-1 has been shown to protect against ethanol-induced hepatocyte damage and increased fatty acid oxidation, thereby preventing fatty liver development in a rat model of NAFLD (19).

Despite the encouraging results obtained for PARP-1 inhibitors in preclinical studies, several obstacles remain in the translation of these discoveries into successful clinical applications. A major issue is the intrinsic disparity between animal or in vitro systems and the intricate pathophysiology of human disease. Preclinical models cannot accurately replicate the tumor microenvironment, genetic diversity or immune responses observed in patients. In addition, drug metabolism and pharmacokinetics differ significantly across species, resulting in variations in efficacy and toxicity profiles. Another major barrier is the development of resistance mechanisms in patients, which are not always predictable from preclinical data (150). Collectively, these factors contribute to the frequent failure of preclinically promising drugs in clinical trials and highlight the requirement for improved prediction models and biomarkers. Nevertheless, PARP-1 inhibition remains a promising treatment strategy for various liver diseases, if these translational challenges can be addressed.

Future expectations

As research has progressed, understanding of the role of PARP-1 in liver disorders has advanced. Studies have shown that conditions such as ALD (52), liver cirrhosis (88) and HCC (94,95) are associated with elevated PARP-1 levels, and that reducing PARP-1 expression and/or activity in hepatocytes can alleviate these disorders. This section of the review examines future directions for PARP-1 research by integrating the latest findings from both medical and and pharmaceutical perspectives.

PARP-1 inhibitors are commonly used to treat malignancies, such as breast and ovarian cancers, with BRCA1/2 mutations (151). However, these inhibitors have limited effectiveness in individuals who develop resistance to PARP-1 inhibitors and in other malignancies, such as HCC (152). Therefore, clinical development has focused on overcoming PARP-1 inhibitor resistance.

First, PARP-1 inhibitors can be combined with other DNA damage repair inhibitors. Resistance to PARP inhibitors is often not due to target protein mutations, but arises from the ability of tumor cells to change their DNA damage repair pathways (153). In addition to PARP-1, several other proteins participate in DNA damage repair. For example, DSBs recruit ATM proteins, which mediate checkpoint signaling and DNA repair (154). Replication stress activates ATM and Rad3-related (ATR), which stabilize and restart replication forks, with checkpoint kinases 1 and 2 acting downstream of ATR and ATM (155). The effectiveness of DDR inhibitors as monotherapies depends on their specific biological activity, and combining inhibitors may be a beneficial therapeutic approach when complementary pathways are targeted (156).

Secondly, PARP-1 inhibitors can be combined with immune checkpoint inhibitors. PD-1, PD-L1 and cytotoxic T-lymphocyte-associated antigen-4 are the most studied immunological checkpoints. Immune checkpoint inhibitors targeting these molecules exert antitumor effects by stimulating the tumor immune response (157). Treatment with a combination of PARP and immune checkpoint inhibitors has been shown to exhibit higher antitumor efficacy than monotherapy. Immune checkpoint inhibitors are able to sensitize tumor cells to PARP inhibitors, which represents a promising therapeutic approach (158).

A recent study identified numerous novel liver cancer susceptibility genes and characterized the landscape of rare genetic variants of liver cancer in a Chinese population. These variants were found to be strongly associated with the risk of liver cancer. Notably, the nuclear RNAi-defective 2 (NRDE2) gene was shown to enhance the assembly and activity of the casein kinase 2 complex, thereby promoting the phosphorylation of mediator of DNA damage checkpoint protein 1, initiating the HR repair pathway for DNA DSB repair, and ultimately inhibiting the development of liver cancer. NRDE2 may be a potential synthetic lethal target as rare genetic mutations that impair its HR repair function markedly increase the susceptibility of HCC to PARP-1 inhibitors. Overall, the study demonstrated that NRDE2 is a regulatory component that suppresses HCC and facilitates DNA damage repair, and that its deficiency in HCC cells results in greater susceptibility to PARP-1 inhibitors (159). This study identified NRDE2 as a potential biomarker for the treatment of HCC with PARP-1 inhibitors. However, further studies are necessary to determine whether NRDE2 deficiency could be used as a biomarker for PARP-1 inhibitor response in other cancer types or if the loss of other genes may have an impact comparable to that of NRDE2 (158).

Conclusions

PARP-1 plays a crucial role in liver disease by managing responses to DNA damage, inflammation, apoptosis and metabolic balance. When PARP-1 is dysregulated, it significantly contributes to the progression of conditions such as NAFLD, ALD, viral hepatitis, autoimmune liver diseases, hepatic fibrosis and the serious development of HCC. Research has shown that inhibiting PARP-1 can help reduce liver cell injury, decrease inflammation and fibrosis, and enhance antitumor immunity, highlighting its potential as a therapeutic target. Additionally, combining PARP-1 inhibitors with immune checkpoint blockers or agents that target DNA repair may improve treatment effectiveness. Future research should focus on the specific roles of different PARP-1 isoforms, the mechanisms behind treatment resistance and how to apply these findings in clinical settings. Overall, PARP-1 represents a promising target for both treatment and diagnosis, with the potential to improve outcomes for various liver diseases.

Acknowledgements

Not applicable.

Funding

This study was supported by the Natural Science Research Project of Anhui Educational Committee (grant no. 2024AH050702) and the Anhui Traditional Chinese Medicine Inheritance and Innovation Research Project (grant no. 2024CCCX288).

Availability of data and materials

Not applicable.

Authors' contributions

KH, HT and SC wrote the manuscript. YL and RW created the figures and table. YJ and BC supervised the research, revised the manuscript, obtained financial support, conceptualized the review and performed the literature search. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References