Hepatocytes, comprising a substantial proportion of the liver and orchestrating critical metabolic, synthetic and detoxification processes, exhibit age-associated genomic instability, as supported by current evidence (39). Notably, senescent hepatocytes are prevalent across diverse hepatic pathologies, suggesting their relevance as a mechanism underlying liver disease. Data from murine aging models show that, alongside reduced hepatocyte volume, polyploid and/or aneuploid senescent hepatocytes accumulate extensively in the liver (40). A study identified a hepatocyte subset with high telomerase expression; comparative RNA sequencing analysis of hepatocyte subtypes further revealed that this subpopulation enhances liver regeneration during homeostasis and injury (41). Hence, hepatocytes are relatively resistant to telomere attrition, with the causal link between telomere loss and hepatocyte senescence remaining controversial; a plausible hypothesis thus posits that hepatocyte senescence arises via telomere shortening-independent pathways. Enhanced oxidative stress caused by the imbalance of ROS induces cumulative DNA damage in senescent hepatocytes, a feature prevalent in chronic liver disease among the elderly (42). A recent work using a hepatocyte-specific MDM2 knockout mouse model showed that MDM2 inactivation resulted in p53 accumulation in the hepatocytes, followed by elevated its target gene, the cell cycle inhibitor p21, which is a key sign of senescence (43). A comprehensive study analyzing human clinical samples and in vitro models characterized senescent hepatocyte gene signatures in chronic liver disease. It revealed upregulated expression of key senescence markers, including SASP components, p53, and cell cycle regulators (such as cyclin D), in both cirrhotic liver tissues and experimentally induced senescent HepG2 cells (44).

HSCs, normally quiescent under physiological conditions, are primarily recognized for activating in response to liver injury. Single-cell sequencing has revealed that activated HSCs display marked cellular heterogeneity, with distinct subpopulations exhibiting proliferative, inflammatory, or fibrogenic phenotypes tailored to specific functions (45). Notably, a subset of activated HSCs is considered an important source of the pro-fibrotic and inflammatory effects of the SASP. TGF-β, a core SASP factor, is a master regulator of HSC activation, driving their transdifferentiation into myofibroblasts (46). These transformed cells proliferate and secrete ECM components, excessive collagen deposition (such as Col1a1) and dysregulated MMPs, at the site of injury, which alter the structure of the liver and continue to impair its cellular function (47). Importantly, persistent HSC proliferation, combined with impaired senescence mechanisms creates a permissive microenvironment that drives fibrotic progression and even hepatocellular carcinogenesis. Additional inducers of senescence in activated HSCs have been identified, including increased susceptibility to DNA damage. Moreover, IL-22 upregulation induces HSC senescence while inhibiting α-smooth muscle actin expression. Transcriptomic analyses have comprehensively characterized HSCs senescence in human and rodent models, with findings showing that senescent HSCs originate from activated HSCs (48). HSC senescence is largely absent in healthy livers, but increases with disease progression, these senescent cells interact closely with recruited immune cells, possibly in response to SASP mediators.

LSECs, a distinctive endothelial population in the liver, are regarded as key regulators of hepatic homeostasis (49). With aging, these cells exhibit marked phenotypic dysregulation, characterized by ultrastructural and functional changes. LSECs exhibit pseudocapillarization, an ultrastructural alteration involving reduced fenestration number and size, thereby disrupting the physiological filtration barrier, a phenomenon validated across species including humans, murine models and non-human primates (50,51). This, combined with hepatic aging, contributes to increased mitochondrial oxidative stress, reduced intrahepatic nitric oxide availability, upregulated p16 expression and a moderate pro-inflammatory state, such as enhanced expression of IL-1, IL-6 and TNF-α at the mRNA level, as shown in aged rats and human samples (52). In addition, senescent LSECs exhibit increased expression of cell adhesion markers [such as intercellular adhesion molecule-1 (ICAM-1)], leading to an accumulation of substantial leukocyte and reduced hepatic blood flow. This impairs the liver's ability to balance fibrosis and regeneration, indicating an age-related hepatic inflammatory response (49). Research on LSECs of rats has furthermore shown that aged rats exhibit more pronounced reductions in LSEC fenestrations and impaired injury recovery capacity compared with young counterparts, according to the model of CCl4- and phenobarbital-induced cirrhosis (53).

KCs, the resident liver macrophages of the hepatic sinusoids, constitute 80-90% of the body's total macrophage population. These cells serve as sentinels of hepatic innate and adaptive immunity, and their distribution altering during aging (54). Single-cell transcriptomic profiling has revealed that compared with younger counterparts, hepatic macrophages in aged mice exhibit a heightened pro-inflammatory (M1) phenotype, with markedly upregulated expression of pro-inflammatory cytokine genes such as IL-6, TNF-α and IL-1β (55). Therefore, KCs play a pivotal role in hepatic inflammatory aging, where the M1/M2 polarization ratio reflects age-related functional alterations in macrophages. Aging also attenuates macrophage functions, including the phagocytic clearance of extracellular pathogens and antigen-presenting capacity, which impairs bacterial killing and inflammation resolution (56). This phenomenon explains why, despite similar inflammatory responses in young and aged individuals, the capacity for inflammation resolution is markedly impaired in the elderly, resulting in persistent chronic inflammation. Mechanistically, liver macrophages promote bystander cell senescence through TGF-β1 signaling, thereby accelerating aging-related pathologies (such as fibrosis) during hepatic injury (57). Fontana et al (58) revealed that under identical high-fat diet (HFD) conditions, aged mice exhibit exacerbated hepatocellular injury and inflammatory responses compared with young controls. This age-dependent susceptibility is associated with heightened M1-polarized macrophage infiltration both in hepatic and adipose tissues. Macrophage-targeted therapies may effectively reduce susceptibility to age-associated liver diseases.

Biochemical studies have consistently established the liver as a master metabolic regulator, orchestrating systemic energy balance through hepatic lipid and glucose homeostasis, steroid biosynthesis/degradation and insulin signaling (60). Under homeostatic conditions, cellular ATP is primarily generated from energy substrates (glucose, fatty acids and amino acids) via core biochemical pathways including glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation and amino acid catabolism (61). It is now recognized that dysregulation of these metabolic pathways critically drives chronic liver disease pathogenesis. Single-cell RNA sequencing and proteomic studies have revealed remarkable heterogeneity and plasticity in liver-resident cells. Metabolic reprogramming and bioenergetic shifts within distinct hepatic cell populations drive complex physiological and pathological processes, initiating and sustaining tissue damage while promoting fibrogenesis (62,63). Critically, it remains uncertain whether metabolic dysregulation is a cause or consequence of age-related hepatic pathologies.

It is well established that during liver disease progression, hepatocellular damage and chronic low-grade inflammation induce metabolic reprogramming, which is characterized by dysregulated hepatic metabolism and ectopic lipid deposition (64,65). Growing evidence highlights the pivotal role of aerobic glycolysis in this pathological process. First, aerobic glycolysis promotes a pro-inflammatory state in immune cells, perpetuating hepatic inflammation and injury (66). Second, enhanced aerobic glycolysis sustains HCC progression by facilitating proliferation, metastasis and chemoresistance (67). The pivotal regulatory enzyme pyruvate kinase M2 (PKM2) functions as a central metabolic switch, mechanistically reflecting the Warburg effect observed in hepatocarcinogenesis (65). Experimental and clinical evidence demonstrates that while PKM2 expression is scarcely detectable in healthy livers, its levels are upregulated in HSCs during fibrosis, as well as in KCs and Th17 cells in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) (68,69). Notably, PKM2 expression increases in precancerous cirrhotic livers and is strongly associated with elevated HCC risk. These findings collectively indicate that glycolytic reprogramming acts as a critical driver of HCC precursor lesions and tumor microenvironment remodeling. Intriguingly, glycolysis is augmented during both replicative and oncogene-induced senescence (70). Mechanistically, disturbances in lipid metabolism, amino acid dysregulation, and impaired mitochondrial energy production synergistically promote inflammation and oxidative stress; pathological features that have been validated in the progression of fibrogenesis (71).

Mitochondria function not only as cellular energy hubs but also as potential triggers of chronic inflammation and cell necrosis (72). With aging, mitochondrial function in senescent cells undergoes complex changes due to intertwined mechanisms, including structural damage (such as swelling, loss of cristae definition and inner membrane disruption), accumulation of mitochondrial DNA (mtDNA) deletions and mutations, and electron transport chain (ETC) impairment (73,74). These alterations also increase ROS production, which can damage cellular components through oxidative stress. Importantly, mitochondria are the most abundant organelles in liver tissue and their dysfunction is a common feature of both hepatic metabolic impairment and disease progression (75). Consistent with this, accumulating evidence confirms that mitochondrial dysregulation contributes to the pathogenesis of age-related hepatic disorders and their progression (76,77). These contain metabolic associated fatty liver disease (MAFLD), hepatic fibrosis, cirrhosis and HCC, among others.

Consistent with the microprotein humanin, plasma levels of another mtDNA-encoded microprotein, MOTS-c, also declined with age. Notably, exercise promotes the production of its metabolite 5-aminoimidazole-4-carboxamide-1-β-4-r ibofuranoside, which acts as an endogenous AMPK agonist and protects against age-dependent and HFD-induced insulin resistance, including in MAFLD (78,79). Mitochondrial dysregulation also drives lipofuscin accumulation and increased lipid deposits. Furthermore, lipid-derived aldehydes are also altered in senescent cells. Given these observations, while a strong link between cellular aging and lipid accumulation has been hypothesized, lipid metabolism within senescent microenvironments remains poorly understood. A recent study demonstrated that both HFD and aging induce mitochondrial dysfunction, reduce lipid oxidation, and cause liver damage (80). Specifically, rats with HFD intake or aging show reduced mitochondrial uncoupling, and decreased superoxide dismutase (SOD) activity is accompanied by increased ROS production, which impairs energy substrate utilization. In this scenario, hepatic lipid accumulation is substantial, and increased pro-inflammatory cytokine release from adipose tissue exacerbates liver damage, worsening with age and occurring earlier in HFD-fed models. Aldehyde dehydrogenase2 (ALDH2) is a mitochondrial enzyme that reduces cellular oxidative stress and prevents associated damage. ALDH2 gene mutation or knockout reduces mitochondrial enzyme activity and mitophagy, increases ROS production, and promotes the development of liver fibrosis-related diseases (81).

Adding to its significance, generally, diminished mitophagy is assumed to be a hallmark of liver diseases. Impaired mitophagy has been observed in most cases of chronic alcohol consumption (82). Indeed, the influence of alcohol on mitophagy depends on exposure duration and dose, with acute high-dose intake inducing excessive mitophagy activating PINK1/Parkin or BNIP3-mediated pathways to drive alcoholic hepatitis progression (83). Another study found that autophagy machinery defects in LSECs from NASH patients upregulate inflammatory pathways (including CCL2, CCL5, TNFα, IL-6 and Tgfb1 expression), confirmed in vitro, and inadequate endothelial autophagy exacerbates liver inflammation to drive disease progression (84). Paradoxically, existing reports are conflicting: For example, autophagy acts as a tumor suppressor, as Beclin 1 disruption accelerates hepatitis B virus-induced premalignant lesions and increases malignancy risk, whereas it can promote established tumors by driving metastasis and drug resistance in later stages (85).

Owing to its central role in metabolism and detoxification, the liver exhibits greater susceptibility to oxidative stress than other organs (86). To counteract such insults, hepatic antioxidant defense systems, comprising enzymatic and non-enzymatic components including SOD, glutathione peroxidase (GPx), catalase (CAT) and glutathione reductase (GR), protect the liver microenvironment from oxidative damage while maintaining physiological function (87). However, chronic exposure to physiological and pathological stressors elevates ROS beyond homeostatic thresholds, triggering oxidative damage to DNA, lipids and proteins. This cascade subsequently activates senescence-associated signaling pathways, culminating in irreversible cell cycle arrest (88). Consequently, oxidative stress represents a critical driver of age-related hepatic injury progression.

Proteomic profiling analysis revealed that in the liver of aged Wistar rats, the defense capacity against oxidative stress, microsomal fatty acid oxidation and peroxisomal function are impaired, accompanied by marked downregulation of antioxidant genes (Cyp2C11, Sod2 and Fmo3) (89). Similarly, long-term alcohol consumption markedly upregulated CYP2E1 gene expression via the CB1R-ERγ-FGF23 axis, inducing hepatic oxidative stress and accelerating the progression of alcoholic liver disease (ALD) (90). During aging, excess ROS markedly disrupt the ECM, primarily by impairing MMP activity. This interaction accelerates ECM breakdown and stiffening, dysregulates MMP activity, and enhances collagen cross-linking and deposition in the liver. Collectively, these alterations remodel the hepatic architecture and drive a pro-fibrotic microenvironment conducive to liver fibrosis. Furthermore, reduced levels of the critical anti-aging factor sirtuin (SIRT)1, potentially due to repression by CCAAT/enhancer-binding-protein/histone deacetylase 1 (C/EBPβ-HDAC1) complexes, may contribute to accelerated liver aging (91). Additionally, the age-related decline in the hepatic NAD⁺/NADH ratio further impairs SIRT1 function.

Proteostasis, a delicate dynamic equilibrium among protein synthesis, folding, trafficking and degradation, involves quality control mechanisms whose disruption triggers systemic network failure (92). For instance, cellular stress or tissue damage often leads to misfolded and dysfunctional proteins, which gradually form aggregates. Misfolded proteins are degraded by endoplasmic reticulum (ER)-dependent mechanisms, most prominently the unfolded protein response (UPR) and the heat shock response. Impaired proteostasis is considered hallmark of aging, with research showing that proteostatic capacity declines with age, independent of underlying disease (93,94). The mRNA and protein levels of molecular chaperones, which are essential for protein folding, are markedly reduced with aging. Meanwhile, more and more evidence indicates that UPR-regulated protein degradation critically affects chronic liver disease. For instance, ethanol or HFD could induce hepatic ER stress and activate the UPR, causing severe hepatic oxidative damage, inflammation and apoptosis (95). In addition, heat shock proteins (HSPs) facilitate ER signaling in response to stress stimuli. Analyses showed that the induction levels of HSP70, HSP27 and HSP90 in hepatocytes of aged rats exhibit a marked downward trend (51). Heat shock factor 1 (HSF1), a molecular trigger and transcription factor, controls the heat shock response, which is activated during abnormal cellular events. A recent study shows that HSF1 may increase the accumulation of collagen and promote liver fibrosis, whereas inhibition of this factor delays or attenuates fibrotic progression by suppressing the expression of profibrotic markers and cell proliferation (96). Young individuals counteract protein misfolding caused by diverse stressors through intact chaperone responses and proteolytic systems. By contrast, elderly individuals exhibit depleted proteostatic capacity, leading to impaired adaptive defense and repair under oxidative, inflammatory, or other pathological conditions, thereby accelerating disease progression (97,98).

Epigenetics, a reversible heritable mechanism that regulates gene expression without altering the DNA sequence, represents a key mediator of the complex aging process in response to environmental cues (99). Epigenetic events include DNA methylation, histone modification, chromatin remodeling and non-coding RNA regulation. The human DNA methylation landscape changes with chronological aging: Cytosine-phosphate-guanine (CpG) sites in promoter regions typically undergo hypermethylation, while other genomic CpG sites exhibit hypomethylation (100). This signature is linked to the age-associated progression of fibrosis, cirrhosis and even HCC, as validated across diverse cohorts of liver disease patients (101). RNA-seq and DNA methylation array analyses of liver tissues and peripheral blood leukocytes from HCC patients identified DNA methylation as a regulator of chronic liver disease, mediating tumorigenesis, shaping HCC transcriptional landscapes and influencing disease outcomes (102).

The activation or silencing of gene expression by post-translational modifications of histones is bound up with the aging process, with histone acetylation being the most well-documented. Accumulating evidence indicates that alterations in histone acetyltransferase and histone deacetylases affect cellular transformation and hepatic metabolism, thereby disrupting hepatic function and causing liver injury (103,104). For instance, acetylation of histone 3 and histone 4 is a well-recognized alteration in MAFLD (105). Acetylation of H3K9 and H3K18 activates the transcription of key pro-inflammatory genes (such as TNFα, CCL2 and components of the NF-κB pathway), further triggering or exacerbating the inflammatory response in MAFLD (106). SIRTs, nicotinamide adenine dinucleotide (NAD)-dependent class III HDACs that adapt to metabolic stress, are inactivated, thereby driving the induction of a senescent phenotype. These observations confirm that SIRT1 and SIRT3 are essential for redox homeostasis and hepatic lipid metabolism. Notably, MAFLD patients and individuals with alcohol consumption exhibit reduced hepatic SIRT1 and natural SIRT1 activator supplementation protects against these liver diseases (107). MacroH2A1, one of the molecular targets of SIRT1, exists in two isoforms: MacroH2A1.1 and macroH2A1.2 and is involved in cellular senescence and tumorigenic processes. The enhanced expression of the SIRT1-binding isoform macroH2A1.1 protects hepatocytes from lipid accumulation (108). Forkhead box O (FOXO) is a key transcription factor implicated in aging and is regulated by NAD⁺/SIRT1, promoting the hypothesis that the SIRT1/FOXO axis is a potential target for countering premature cellular senescence and hepatic pathology. In addition, perturbed SIRT3 function in mice is associated with MASLD-like abnormalities and SIRT3 knockout mice are prone to metabolic dysfunction-associated steatohepatitis (MASH) development. Beyond these mechanisms, in vivo metabolic tracing has demonstrated that histone methylation and phosphorylation in intrahepatic cells also contribute to the development of ALD (109).

Non-coding RNAs (ncRNAs) constitute a diverse class of regulatory molecules that have emerged as epigenetic factors affecting aging, including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) (110). Their ubiquitous presence in the tissues and biological fluids of different species under diverse pathological conditions underscores their significant role in liver biology. Among the mechanisms regulating fibrogenesis, miRNA-mediated pathways, which operate through senescence-associated regulatory protein control, have been the most extensively studied. In MAFLD and HCC, for instance, miR-21 overexpression increased p53 activity (a protein that normally suppresses cell cycle proteins and lipogenesis) (111). Notably, alongside increased miR-221 expression in hepatitis C virus (HCV) infection, miR-221 is elevated in MASH-associated fibrosis (112). Besides, expression levels of miR-19a, miR-19b, miR-122, miR-125b, miR-192 and miR-375 are increased in MAFLD individuals (113). Fortunately, unlike DNA mutations, these regulatory and often reversible changes enable the design of new anti-aging therapies.

Hepatitis B virus (HBV), a member of the Hepadnaviridae family, causes liver damage through acute and chronic infections. The latter accounts for the vast majority of severe disease burden (115). While HBV infection rates are highest in infancy and childhood, chronic progression occurs in only ~5% of adults infected later in life due to reduced exposure risk. By contrast, elderly patients exhibit markedly higher rates of progression to chronic hepatitis B (CHB) following disease onset, compared with <5% in younger individuals (116). An outbreak investigation of acute HBV in a Japanese nursing home revealed nearly 60% chronicity among patients aged >65 years (117). Moreover, advanced age is a risk factor not only for cirrhosis progression but also for HCC development. This phenomenon may be attributed to an age-related decline in pathogen-specific immune responses, warranting further research to elucidate the underlying pathophysiology and immunological mechanisms in this population.

Age-dependent telomere attrition serves as a robust indicator of the cumulative effect of cellular aging on inflammation in HBV infection. Available evidence indicates that peripheral blood mononuclear cells lose ~50 bp of telomeric DNA per year on average, however, this loss is likely to increase during chronic viral infections (118). Notably, in CHB, hepatocytes exhibit elevated p21 expression and G₁ phase arrest, indicating the presence of p21-mediated G₁ arrest and all indicative of a strong senescent response. For example, telomere length measurements in HBV, performed in hepatocytes, showed shorter telomeres in both liver biopsy tissue and peripheral blood lymphocytes of HBV-infected patients (119). Consistent with this, another study identified fewer and shorter telomeres in CHB patients compared with matched controls (120), whereas both symptomatic and asymptomatic HBV-positive individuals exhibited elevated serum telomerase activity, probably countering telomere shortening-induced cellular senescence (121). Extensive hepatocyte telomere shortening aligns with accelerated aging, telomere length is comparable to that of individuals with normal aging of 10 years and can be extended to 15 years in the case of more severe fibrosis in this pathological context, which helps to explain, at least in part, the pathological features of accelerated aging (122).

The mechanistic crosstalk between telomere attrition and DDR is well-established and underpinned by persistent DDR activation that, when surpassing cellular repair capacity ultimately triggers premature senescence. Existing data demonstrate that aged liver samples exhibit aberrant DNA methylation at multiple loci, this pattern of epigenetic alteration is further exacerbated in CHB. An earlier study revealed more pronounced DNA damage in peripheral lymphocytes from HBV patients (123). As aforementioned, the pathology of cellular senescence is involved in the phenotypic alterations of infected cells, a notion that at least partially justifies some conflicting findings. For instance, although most HBV-encoded proteins drive aging or enhance hepatocarcinogenesis risk, HBx represents an exception: Methylated HBx downregulates p16^INK4a and p21^Waf1/Cip1, inactivates Rb phosphorylation and thereby enables escape from cellular senescence (124). Notably, another study on the interaction between HBV and cellular senescence in patients with CHB, in which HBx is not involved as a key player (125).

Beyond this, early-life HBV exposure induces premature immunosenescence. Specifically, viral-mediated inhibition of topoisomerase I induces topological DNA damage and telomere attrition in CD4⁺ and CD8⁺ T cells. Epidemiological studies on HBV-endemic individuals carrying the HBV-specific T-cell marker TCR Vβ12, revealed lower CD3⁺ and CD4⁺ T-cell counts, indicating impaired immune function from CHB (126). Mechanistic studies demonstrated that in a mouse model of HBV persistence-induced systemic tolerance, hepatic CD4⁺ T cells continuously produce IFN-γ, which stimulate CXCL9 secretion by KCs to facilitate CXCR3-dependent retention of antiviral CD4⁺ T cells, ultimately driving their apoptotic clearance (127).

Age-related immunosenescence and immune checkpoint dysfunction profoundly influence HBV pathogenesis. Under physiological conditions, harmful senescent cells are cleared by recruited immune cells, such as monocytes and macrophages. During aging, nevertheless, immune surveillance and host defense mechanisms become widely suppressed and rendered ineffective in HBV, resulting in insufficient clearance of senescent and precancerous cells, a process that appears to play an important role in carcinogenesis (126,128). In vivo and in vitro findings indicate elevated SASP levels in chronic HBV infection, with excessive secretion of its components (growth factors, interleukins and MMPs) promoting HBV-associated HCC development, an effect exacerbated by aging (129). Compared with HBV-negative HCC cells, HBV-positive cell lines showed increased MMP-9 expression, reduced tissue inhibitor of metalloproteinase expression and higher invasive potential (130). Similarly, HBsAg-positive patients have higher peripheral blood TNF-α and IL-6 levels (131). Of note, consistent with these findings, a clinical study conducted by Rosenberg et al (132) found that donor-derived T cells from older donors exhibit reduced hepatitis B surface antigen-specific proliferative response, while younger donors show stronger responses.

MAFLD, previously termed as NAFLD, is characterized by hepatic steatosis and affects up to one-third of the global population. While the age of MAFLD onset has decreased in recent years, its prevalence, risk of hepatic/extrahepatic complications and rates of all-cause and disease-specific mortality increase with advancing age (133). Moreover, geriatric patients harbor more MAFLD risk factors, including hyperlipidemia, obesity, diabetes and hypertension and exhibit more severe biochemical, hematological and histological alterations than younger cohorts. A cross-sectional analysis of adult participants found that elderly patients with MAFLD had a higher likelihood of MASH and advanced fibrosis compared with younger adults (134). The detrimental effect of aging on hepatic homeostasis manifests through cellular-level structural damage, progressive decline in liver function and metabolic dysregulation. Extensive research indicates that MAFLD-associated pathological changes, including abnormal hepatocyte morphology, lipofuscin accumulation and ECM deposition, are associated with accelerated liver aging, potentially driving age-related hepatic steatosis. Notably, Gao et al (135) demonstrated that lipid accumulation directly exacerbates hepatic aging. These findings suggest that the pathogenesis of MAFLD may be intrinsically linked to biological aging. However, whether cellular senescence initiates or results from hepatic metabolic dysfunction and inflammation remains unresolved.

Clinical and preclinical evidence supports a link between cellular senescence and MAFLD. Senescent hepatocytes are more abundant in patients with MAFLD and, as observed in other chronic liver diseases, their senescence levels correlate with the severity of MAFLD, as confirmed by liver biopsies in these patients (136). Several markers of senescence, such as SA-β-Gal, p16, p21 and p53, are elevated in individuals with MAFLD/MASH (137). Similarly, rodent studies demonstrate that HFD reduces the phosphorylation of Rb by upregulating p16 and p21, inducing hepatocyte cell cycle arrest, activating senescence pathways, and ultimately promoting MAFLD (138). Analogously, in p53-null mice, inhibition of p66Shc signaling reduces hepatic lipid peroxidation and hepatocyte apoptosis, delaying nutritional steatohepatitis development (139). Meanwhile, a similar effect occurs after the systemic clearance of p16-expressing cells. DNA methylation additionally serves as a key mechanism: In high-fructose/high-cholesterol-fed mice, its patterns alter liver lipid gene expression (upregulating lipid genes and downregulating proliferation/transcription genes) and specific histone modifications induce proliferation arrest (140). Other markers of senescence (genomic instability and DNA damage), are also directly associated with the progression of MAFLD.

Of great importance, immune system aging is closely linked to MAFLD/MASH via proinflammatory factor secretion. The local microenvironment and the aging immune cell population engage in a vicious cycle, the resultant inflammatory milieu triggers and amplifies microenvironmental responses, thereby exacerbating hepatic dysfunction. A recent pivotal study identified that marked hepatic T-cell senescence and exhaustion drive metabolic liver disease progression in humans (141). Specifically, in contrast to normal individuals, patients with MASH show upregulated expression of senescence- and exhaustion-related genes in hepatic CD4⁺ and CD8⁺ T cells, along with increased expression of IL-2, IL-15 and IL-18 in these cells. Hepatic macrophage accumulation relies on CCL2-CCR2-mediated chemotaxis: M1 activation (marker CD86) is associated with MAFLD severity in humans, and older mice show more pronounced M1 infiltration in both liver and adipose tissue (142).

ALD is a globally prevalent condition driven by chronic excessive alcohol consumption, posing a serious health threat to ~75 million individuals (143). Alcohol metabolites generated during hepatic processing produce toxic substances that trigger hepatocyte inflammation and severe liver damage via inflammatory cascades involving cytokines, chemokines and ROS (144). Evidence indicates higher rates of binge drinking among middle-aged and older adults, with the risk of alcohol abuse being further elevated by age-related metabolic changes, smoking, or illicit drug use. Chronic low-grade inflammation in older adults, characterized by elevated circulating pro-inflammatory cytokines and tissue inflammatory cell infiltration, exacerbates ALD progression (145). Concurrently, emerging evidence demonstrates that ALD accelerates cellular senescence. Murine ALD models show increased senescence-associated biomarkers, such as miR-34, p16, p21 and p53, along with elevated SASP factors (TGF-β1, PAI-1 and CCL2) (146). Additionally, ALD patients exhibit significant hepatic telomere shortening, accompanied by upregulation of telomere-binding protein genes, which suggests a compensatory response to DNA damage (147).

Notably, immunosenescence plays a central role in ALD pathogenesis through senescence-associated regulatory mechanisms. Following chronic ethanol exposure, activated immune cells trigger cytokine and chemokine production, initiating a pro-inflammatory cascade (148). Current evidence indicates that most KCs polarize predominantly toward pro-inflammatory M1 phenotypes, releasing abundant cytokines including IL-1β, IL-18, TNF-α, IL-12 and IL-23. These mediators induce potent innate immune responses and critically contribute to alcohol-induced liver injury. By contrast, activated M2 macrophages increase in number and secrete abundant anti-inflammatory factors during tissue repair following injury (149). Nevertheless, macrophage polarization remains vaguely defined and controversial due to the inherent plasticity of these cells and their context-dependent responses to pathological signals. Notably, Wan et al (150) demonstrated that M2-polarized macrophages induce hepatocyte senescence via IL-6 secretion, accelerating alcohol-induced senescence both in vivo and in vitro Extensive evidence indicates that chronic ethanol exposure alters T-cell immunophenotypes in mice and humans. Liver biopsy specimens from patients with moderate-to-severe ALD reveal significant CD3⁺ T cell infiltration and activation (including CD4⁺ and CD8⁺ subsets) (151) Compared with controls, T cells from alcohol-fed mice produce elevated levels of IFN-γ and IL-4. A pronounced Th1-dominant response promotes ALD progression through IL-2, TNF-α, and IFN-γ production, while Th17 cells exacerbate liver damage via IL-17 secretion. Notably, Th17 cell populations expand with aging, and Th17-derived IL-17 enhances SASP production, thereby amplifying the inflammatory cascade (152).

Liver fibrogenesis constitutes a highly integrated, dynamic process involving molecular, cellular and tissue-level changes. This process is primarily characterized by excessive ECM deposition, driving extensive disruption of hepatic architecture and functional integrity (153). Organ fibrosis represents a hallmark manifestation of chronic inflammatory disease progression, accounting for ~45% of global all-cause mortality. Accordingly, hepatic fibrosis development critically determines both disease prognosis and patient quality of life (154). The aging global population and the rising prevalence of fibrosis-predisposing conditions (including viral hepatitis, MAFLD, ALD, primary sclerosing cholangitis and autoimmune hepatitis) are driving the growing burden of liver fibrosis. Regardless of etiology, clinical severity escalates substantially with fibrotic septa formation and progression toward cirrhosis, leading to increased mortality and HCC incidence. Globally, liver diseases account for 1.5-4% of annual deaths (155,156). Experimental and clinical studies have demonstrated that matrix remodeling and partial architectural restoration can occur even in advanced fibrosis/cirrhosis, suggesting this stage represents a potential therapeutic window in chronic liver disease progression (157). Thus, targeted investigations of the underlying pathophysiological mechanisms are needed.

Fundamentally, fibrosis is not a unidirectional process but rather a dynamic interplay of factors including persistent inflammation, dysregulated ECM remodeling, and myofibroblast formation and proliferation during tissue wound healing and fibrogenesis (158). Aging populations exhibit increased susceptibility to irreversible fibrotic damage due to a diminished wound-healing capacity and impaired fibrosis resolution. Substantial emerging evidence indicates that established biomarkers of cellular senescence in liver tissue (such as miR-378, miR-18b-3p and the lncRNA-ATB/miR-200a/β-catenin axis) are elevated in patients with liver fibrosis and cirrhosis, underscoring the role of senescence in the pathogenesis of these disorders (159). The SASP drives fibrosis by establishing a pro-inflammatory and pro-fibrotic microenvironment. Wijayasiri et al (160) found that HSCs exposed to conditioned media from senescent HepG2 cells exhibited activation and secreted abundant inflammatory and fibrotic mediators. HSC activation represents a key pro-fibrotic consequence of the SASP. Furthermore, during fibrotic progression, activated HSCs can undergo spontaneous senescence. TGF-β key component acts as a potent activator of HSCs, driving their transformation into myofibroblast-like cells and promoting excessive ECM protein production. Notably, immune defenses are compromised in aging patients with fibrosis, increasing susceptibility to inflammation and infection-related complications (161). The recruitment of abundant immune cells (neutrophils and macrophages) to the liver via elevated pro-inflammatory SASP factors, including IL-6, IL-8 and TNF-α, perpetuates cycles of oxidative stress, inflammation and fibrosis, a phenomenon that intensifies with aging. Single-cell transcriptome analyses have revealed expanded populations of CD4⁺ T cells, CD8⁺ T cells and γδ T cells in fibrotic liver tissue, with further increases observed in cirrhosis (162). Typically, Th1 and Th17 cells accelerate fibrotic progression by acting on hepatocytes, KCs and HSCs through pro-inflammatory mediators. By contrast, substantial evidence indicates that Treg cells exert antifibrotic effects, partly mediated by IL-10-dependent immunosuppression (163). In brief, the convergence of inflammation, immune cells mobilization, and activation of HSCs and hepatocytes drives both liver fibrosis and aging-related pathology.

Additional links between cellular senescence and fibrosis include telomere attrition and mitochondrial dysfunction. Dysregulation of the mitochondrial ETC drives oxidative stress, damaging cellular components and promoting fibrogenesis. Besides, the age-related decline in mitochondrial function predisposes the liver to heightened stress sensitivity and fibrosis susceptibility. In accordance with this, substantial release of mtDNA and mitochondria-derived damage-associated molecular patterns has been observed in both human patients and CCl4-induced mouse models with significant liver fibrosis, directly implicating mitochondrial dysfunction in fibrotic pathogenesis (164,165). Given the age-dependent prevalence of hepatic fibrosis/cirrhosis and the established role of telomere attrition as a biomarker of biological aging, replicative senescence is likely to contribute to fibrosis/cirrhosis pathogenesis. Calado et al (166) demonstrated that telomerase abnormalities are associated with hematological disorders and severe liver diseases characterized by fibrosis and inflammation. In line with this, a cross-sectional study revealed an inverse correlation between telomere length and cirrhosis severity, while mutations in telomerase-related genes were identified as cirrhosis risk factors (167,168). Of great importance, emerging evidence positions telomere attrition as a genetic determinant of cirrhosis susceptibility (169).

HCC, as the predominant form of primary liver cancer, accounts for ~90% of hepatic malignancies. Its development is associated with multiple risk factors, including chronic alcohol consumption, persistent viral infections (such as HBV/HCV), chemical exposures, and metabolic disorders (170). Regardless of etiology, hepatocarcinogenesis typically involves recurrent cycles of hepatocellular injury, inflammation and necrosis, processes exhibiting marked molecular and cellular heterogeneity and irreversibility (171). According to GLOBOCAN data, the global incidence of liver cancer reached 906,000 new cases with 830,000 mortalities annually, reflecting rapidly rising rates that impose a substantial global health burden (172). Epidemiological studies consistently demonstrate an age-dependent increase in HCC incidence, with markedly higher rates in individuals over 75 years (173). Notably, older adults may develop HCC even in the absence of fibrosis or cirrhosis, probably due to age-related physiological and metabolic alterations, underscoring the direct role of aging in hepatocarcinogenesis (174).

HCC predominantly arises from persistent viral infections or sterile inflammation These pathological states impair telomerase activity, accelerate telomere shortening, induce hepatocyte malignant transformation and foster a pro-tumorigenic microenvironment. Crucially, senescent cells act as key initiators of this process, serving as chronic inflammatory foci throughout the natural course of the disease (175). Senescent hepatocytes disrupt the local microenvironment through sustained secretion of proinflammatory mediators. These cell populations engage in a self-perpetuating cycle with their microenvironment: Inflammatory signaling induces senescence, which further amplifies microenvironmental inflammation and exacerbates hepatic dysfunction. For example, Li et al (176) revealed that the activation and senescence of HSCs were observed in both human and murine liver tumors, concomitant with SASP secretion. Similarly, in diethylnitrosamine (DEN)/CCl4 -induced HCC models, senescent hepatocytes upregulate SASP secretion (especially IL-8) during hepatocarcinogenesis and a similar phenomenon is observed in human HCC tissues (177). Furthermore, cellular senescence in this context can be prematurely induced by diverse stressors or naturally by replicative exhaustion. Research from Ho et al (178) found that aged mice with senescent β-catenin-deficient hepatocytes developed an inflammatory microenvironment that promoted HCC progression. Intriguingly, as aforementioned, the pathological role of cellular senescence is also environment-dependent, which partly explains some conflicting findings. Senescence is proposed to function as a physiological tumor-suppressive mechanism by recruiting immune cells and inhibiting the progression from benign to malignant lesions in early disease. Therefore, its complex role in cancer needs to be studied under specific conditions.

Indeed, age-related immune dysregulation and immunosenescence profoundly affect the long-term HCC prognosis. As HCC progresses to advanced stages, multiple hepatic cell types, such as immune cells, hepatocytes and endothelial cells, acquire senescence-associated phenotypes, driving systemic failure of antitumor defenses in HCC patients. This process is age-exacerbated, driven by inflammatory cascade signaling and amplified SASP production. RNA sequencing of treatment-naïve HCC tumor has revealed increased Tregs and exhausted CD8⁺ T cell accumulation (179). Comparative analyses further showed elevated levels of Tregs and CD25⁺ CD4⁺ T cells in the peripheral blood of HCC patients compared to healthy individuals, with higher serum immunosuppressive cytokines (TGF-β1 and IL-10) (180). Paradoxically, a meta-analysis showed that higher infiltration of neutrophils and Tregs were correlated with improved overall and disease-free survival, suggesting context-dependent immune roles (181). Notably, tumor-associated macrophages within the tumor microenvironment display aberrant activation. Another study found that M2 macrophages, along with Tregs, Th2, and Th17 cells, increase with HCC progression, and produce elevated levels of IL-6, VEGF, Arg1 and IDO, thereby promoting immune evasion and tumor progression (182).

Senolytics, which encompass small molecules, peptides and antibodies, selectively eliminate senescent cells while sparing normal proliferating cells. These agents induce apoptosis in senescent cells by targeting key survival pathways known as senescent cell anti-apoptotic pathways, including p53, p21 and PI3K/Akt signaling, BCL-2 family members, HSP-90 and other targets (21). Recent systematic screening approaches have identified numerous senolytic compounds with therapeutic potential.

The first-generation senolytic combination of dasatinib and quercetin (D+Q) induces more potent apoptosis and ameliorates age-related pathologies compared with either compound administered alone. Preclinical studies demonstrate that D+Q alleviates multiple age-related conditions in mice, including insulin resistance, hepatic steatosis, pulmonary fibrosis and chronic kidney disease (184,185). Mechanistic studies in aged mice have revealed that D+Q triggers apoptosis in senescent hepatic progenitor cells, effectively reducing senescence-associated phenotypes including reduced SA-β-gal activity and clearance of p16^INK4a-positive cells in the liver (186). Additional evidence confirms that this senolytic combination attenuates hepatic steatosis and ameliorates MAFLD pathology in HFD-induced models (187). Conditional knockout of fructose-1,6-bisphosphatase 1 (FBP1), a key tumor-suppressive metabolic enzyme, induces hepatic metabolic dysregulation in mice. This promotes HSC senescence, which accelerates hepatocarcinogenesis via SASP mechanisms. Li et al (176) demonstrated that intermittent D+Q treatment selectively eliminated senescent HSCs in hepatocyte-specific FBP1-deficient mice, thereby halting HCC progression. Moreover, D+Q reduced HCC-associated gene expression in Sod1^−/− mice and markedly lowered HCC incidence (188). While this senolytic regimen shows therapeutic potential, its precise mechanisms require further exploration. Paradoxically, another preclinical study reported that D+Q exacerbated liver histopathology and tumorigenesis, accelerating disease progression without effectively clearing senescent cells (189). Given the exclusively preclinical evidence regarding D+Q and liver interactions, rigorous studies are warranted to evaluate therapeutic efficacy, while human safety profiles require thorough assessment.

The BCL-2 family proteins, including BCL-2, BCL-X_L, and BCL-W, serve as key regulators of cellular survival and death. These proteins are upregulated during senescence across diverse cell types, establishing them as prime targets for senolytic therapies (190). ABT-263 (navitoclax), a pan-inhibitor of BCL-2 family proteins, suppresses tumor metastasis and recurrence by eliminating chemotherapy-induced senescent cancer cells and hepatocytes within the tumor microenvironment. Preclinically, its demonstrated dose-dependent pro-apoptotic effects against HCC in vitro have now been validated in a phase I clinical trial (NCT01364051) involving HCC patients (191,192). Gold et al (193) recently established that ABT-263 clears senescent stellate cells and hepatocytes in ALD mice, concomitantly attenuating hepatic triglyceride deposition. Ex vivo analyses confirmed caspase-3-mediated apoptosis in acetaldehyde-induced senescent hepatocytes following ABT-263 treatment. ABT-737, a precursor to ABT-263, exhibits senolytic activity in experimental models. In murine models, ABT-737 synergistically enhances sorafenib-induced apoptosis in hepatoma cells, with the combination therapy demonstrating superior suppression of xenograft tumor growth compared with sorafenib monotherapy (194). However, ABT-737 lacks oral bioavailability and exhibits low aqueous solubility. Structural optimization subsequently yielded its derivative ABT-263, which was developed as an orally bioavailable BCL-2 inhibitor (195). Targeted inhibition of BCL-X_L may mitigate side effects (such as thrombocytopenia and neutropenia) associated with pan-BCL-2 inhibition while preserving therapeutic efficacy (196). Indeed, BCL-X_L inhibitors A-1331852 and A-1155463 demonstrate senolytic effects in senescent HUVECs and human lung fibroblasts (196). Although Cucarull et al (197) reported that A-1331852 restored regorafenib efficacy (a second-line HCC therapeutic) in both xenograft models and in vitro systems, BCL-X_L inhibitors remain underexplored for liver pathologies. Further studies are needed to evaluate their safety and efficacy profiles. Overall, BCL-2 family inhibition represents a mechanism-based strategy for senolytic discovery, however, their associated side effects hinder clinical translation.

Research has revealed that forkhead box protein O4 (FOXO4) regulates senescent cell viability by binding and sequestering nuclear p53, thereby inhibiting apoptosis. Based on this mechanism, a retro-inverso peptide, FOXO4-D-retro-inverso (FOXO4-DRI), was developed to disrupt FOXO4-p53 interaction and selectively induces apoptosis in senescent cells (198). Furthermore, FOXO4-DRI conferred protection against doxorubicin-induced accelerated senescence and hepatic damage in mice, suggesting its potential as a therapeutic strategy against senescence-driven liver pathologies (199). However, the short in vivo half-life of FOXO4-DRI necessitates development of stabilization approaches or alternative p53-activating strategies for effective senescent cell clearance.

As HSP90 is a cancer-promoting protein that regulates apoptosis, proliferation and angiogenesis, its inhibition has emerged as a validated strategy for cancer chemotherapy (200). Several HSP90 inhibitors, including 17-DMAG (alvespimycin), 17-AAG (tanespimycin), ganetespib and geldanamycin, exhibit senolytic effects across multiple senescent cell types through distinct, cell-type-specific mechanisms. For example, 17-DMAG suppresses HCC cell proliferation in a time- and concentration-dependent manner, probably by modulating cyclin D1, p53 and NF-κB protein levels (201). Mechanistically, studies indicate that 17-DMAG induces apoptosis in senescent cells, partially through disruption of the HSP90-AKT interaction and impairment of AKT activation (202-204). In both chronic and acute models of alcoholic liver injury, 17-DMAG attenuated oxidative stress and modulated inflammatory responses (205). Another HSP90 inhibitor, ganetespib (STA-9090), was well-tolerated in a phase I dose-escalation trial involving patients with advanced HCC who had progressed after at least one line of systemic therapy, though it did not confer significant clinical benefit (206). However, subsequent preclinical studies revealed that the ganetespib-sorafenib combination synergistically enhanced cytotoxicity by disrupting HIF-1α stability, increasing p62 accumulation, and inhibiting autophagy, thereby augmenting sorafenib monotherapy efficacy (207). Collectively, these findings indicate that sustained research is essential to maximize the clinical translation potential of this therapeutic combination. Critically, precise identification of the dominant senolytic mechanisms in each disease context is essential, as these mechanisms vary markedly across cell types.

Several natural products and their derivatives, including fisetin, piperlongumine and matrine, also possess senolytic properties. For example, fisetin acts through multimodal mechanisms by targeting key regulators such as the PI3K/AKT, BCL-2, p53 and NF-κB signaling pathways (208). In a Lieber-DeCarli ethanol diet-induced ALD mouse model, fisetin alleviated age-related pathologies and improved the local tissue microenvironment in vivo via anti-inflammatory and anti-fibrotic mechanisms (209). Sundarraj et al (210) discovered that fisetin dose-dependently reduced autophagic flux by activating the PI3K/AKT/mTOR signaling and modulating the AMPK pathway, thereby showing therapeutic efficacy against HCC. Piperlongumine, a natural amide alkaloid from long pepper, selectively induces senescent cell death by increasing ROS production and inhibiting PI3K/AKT and NF-κB pathways. It also exerts hepatoprotective and anti-fibrotic effects in bile duct ligation (BDL)-induced liver fibrosis model (211). Due to its biological characteristics, the precise senolytic mechanism of piperlongumine remains unclear. Researchers have developed several piperlongumine analogues (compounds 47-49) through a series of structural modifications. These analogs exhibit enhanced senolytic activity and modulate multiple antioxidant enzyme expressions (212). Nonetheless, most natural compounds exert multi-target, multi-pathway effects, making it challenging to attribute their therapeutic benefits exclusively to senescent cell clearance. Moreover, since senescent cells exert context-dependent beneficial effects, selectively targeting the SASP may represent a safer and more effective anti-aging strategy.

While completely halting physiological aging remains unrealistic, modulating pathways associated with premature senescence represents a promising therapeutic strategy to counteract accelerated aging in liver disease. Senomorphics inhibit detrimental effects of SASP without inducing senescent cell death. In general, these agents suppress SASP expression by targeting key signaling pathways, including mTOR, NF-κB, SIRT1/SIRT3 and JAK. thereby inhibiting cellular senescence (221). While less targeted than senolytics, this approach represents viable intervention strategy.

Originally developed as an anti-fungal agent, rapamycin (sirolimus) ranks among the best-established senomorphic compounds for modulating aging and suppressing the SASP. In multiple animal models, rapamycin has been found to extend lifespan not only in worms and drosophila, but also to increase both median and maximum lifespan in mice when administered later in life (222,223). Evidence confirms that rapamycin effectively suppresses SASP markers, reduces cellular senescence and thereby ameliorates age-related functional decline or delays tumorigenesis in rodent models (224). Mechanistically, rapamycin primarily inhibits mammalian target of rapamycin complex 1 (mTORC1), although chronic administration also attenuates mTORC2 signaling, while potently blocking the translation of membrane-bound IL-1α. This reduction in IL-1α suppresses NF-κB transcriptional activity, consequently inhibiting secretion of most SASP components (225). Notably, the mTOR signaling pathway has expanded markedly beyond coordinating cellular growth and metabolism in response to nutrient availability, and now includes the regulation of aging processes, particularly cellular senescence. Additional mechanisms by which rapamycin may modulate aging, such as nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation, are under investigation. Lee et al (226) investigated the therapeutic effects of rapamycin in transgenic mice with HCC induced by activated HrasG12V and p53 suppression. A low-dose of rapamycin effectively prevented HCC initiation but failed to inhibit established tumor growth. This stage-specific efficacy was mechanistically linked to the expansion of CD4⁺ Tregs and suppression of mTOR downstream targets (including 4E-BP1 and S6K1). Similarly, oral administration of rapamycin effectively inhibits activated hepatic mTOR in ALD mice and inhibits thioacetamide-induced liver fibrosis (227,228). In HFD-induced mice, rapamycin suppresses pro-inflammatory NFκB signaling by increasing p65 and IκBα interaction (229). Regrettably, chronic mTORC1 inhibition via long-term rapamycin administration increased hepatic inflammation and liver tumor incidence (230). Besides, rapamycin and its analogs exhibit various side effects (including pneumonitis, immunosuppression, kidney toxicity and thrombocytopenia and impaired wound healing) complicating long-term therapeutic use (231) Developing next-generation rapamycin analogs may overcome these adverse effects while improving potency and pharmacokinetic profiles.

Metformin, the first drug evaluated in the Targeting Aging with Metformin trial, modulates multiple aging pathways including inflammatory regulation, oxidative stress defense and proteostasis. For example, metformin reduces SA-β-gal activity and downregulates senescence markers across diverse senescent cell types (232). It protects against liver injury in acute viral hepatitis by regulating mTORC1 signaling and mitochondrial function to control effector T-cell activation. Metformin is also well-tolerated in NAFLD patients, though its effects on senescence phenotypes remain unassessed in these contexts (233,234). Metformin activates the adenosine monophosphate-activated protein kinase (AMPK) pathway, demonstrably preventing age-related loss of hepatic sinusoidal fenestration through chronic treatment in young mice and reversing this via acute treatment in aged mice, as shown in LSECs (235). It could be hypothesized that the effect of metformin on LSECs may contribute to the beneficial outcomes of AMPK agonists for liver fibrosis treatment. In vitro studies reveal that metformin suppresses HepG2 cell proliferation by inducing cell cycle arrest at the G₀/G₁ phase, as evidenced by elevated KLF6/p21 protein levels and enhanced AMPK activation (236). This provides a basis for metformin's therapeutic potential in HCC. Corresponding clinical data reveal that prediagnostic metformin use markedly prolonged overall survival in older patients with HCC and type 2 diabetes (237). However, while metformin regulates senescence, its broader effects against age-related pathologies likely involve both senescence-dependent and -independent mechanisms.

SIRT1 expression declines with age, yet its increased expression attenuates cellular senescence and prolongs longevity across species. Resveratrol, a natural SIRT1 activator, exerts therapeutic effects against obesity, tumorigenesis and age-related organ dysfunction (238). As a senomorphic and antioxidant agent, resveratrol prevents cellular senescence by activating telomerase via the PI3K-Akt pathway (239). Additionally, it suppresses SASP factors by inhibiting NF-κB signaling while upregulating the antioxidant Nrf2 pathway. In inorganic mercury-induced liver fibrosis, resveratrol activates the SIRT1/PGC-1α pathway, alleviating oxidative stress and suppressing hepatic stellate cell activation (240). Across multiple human HCC cell lines, resveratrol inhibits viability, proliferation, invasion and migration in a time- and dose-dependent manner by activating p53 and suppressing the PI3K-Akt signaling (241,242). At high concentrations, however, resveratrol exerts pro-oxidant effects inducing growth arrest, senescence, or apoptosis (243). While resveratrol extends organismal lifespan, its murine effects are context-dependent, markedly prolonging survival in HFD models but not in standard-diet controls (244). Besides, the poor bioavailability and instability of resveratrol necessitate developing structurally distinct SIRT-activating compounds. SRT1720, which is 1,000-fold more potent than resveratrol, extends lifespan in HFD mice (22). It demonstrates therapeutic efficacy against both MAFLD and ALD, though its mechanisms remain incompletely characterized (245,246).

NAD⁺, an upstream regulator of SIRT1, modulates both the SIRT1 and NF-κB pathways. These pathways antagonize each other in inflammatory and metabolic processes and critically regulate pathogenic mechanisms in MAFLD progression (247). The senomorphic NAD⁺ precursor NAM improves metabolic function in ALD mice by inhibiting cellular senescence and suppressing SASP production, while reducing liver injury markers (193). Although NAM shows promising therapeutic potential, its adverse effect profile and optimal dosage require careful evaluation. Further trials are needed to establish safe regimens and assess long-term patient outcomes.