Epigenetic Regulation of Liver Fibrosis: Mechanisms and Therapeutic Implications

Hepatic stellate cells in alcoholic liver cirrhosis: mechanisms of fibrogenesis, plasticity, and fibrosis reversal

Modulation of Inflammation-Driven Hepatocarcinogenesis: The Hepatic Immune Microenvironment, Gut–Liver Axis, and Neuroregulation

Abstract Hepatocellular carcinoma (HCC) is a highly malignant cancer closely related to the chronic inflammation induced by persistent liver damage. Various risk factors, including chronic hepatitis B/C virus infections, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease, aflatoxins exposure, and metabolic disorders, contribute to genetic mutations in hepatocytes, leading to sustained cellular damage and apoptosis. These processes foster a chronic inflammatory microenvironment that activates hepatic stellate cells, promotes extracellular matrix deposition, and triggers aberrant regenerative repair, ultimately advancing liver fibrosis, cirrhosis, and HCC. The transition from chronic liver injury to HCC is governed by two interconnected mechanistic layers: initiating triggers—viral infection and hepatocyte death—that provide the substrate for malignant transformation, and modulatory systems that determine the trajectory of this process. Recent studies have revealed that diverse cell types and molecular signaling pathways form an intercellular regulatory network that fosters an inflammatory and carcinogenic microenvironment. This review focuses on three such modulatory systems—the hepatic immune microenvironment, the gut–liver axis, and neuroregulation—and examines how their interplay influences malignant behaviors including cell transformation, proliferation, and apoptosis. We systematically overview the key cellular constituents, fundamental molecular mechanisms, and core signaling pathways governing inflammation-induced hepatocarcinogenesis, and discuss potential therapeutic targets emerging from current research. A deeper understanding of these fundamental pathological mechanisms provides a conceptual framework for elucidating the initiation and progression of HCC. It also offers a theoretical basis for the future development of preventive and targeted therapeutic strategies, although the translation of these mechanistic insights into clinically effective interventions—particularly for cancer prevention—will require rigorous validation in large-scale, prospective human studies.

Understanding the role of hypoxia inducible factors in liver fibrosis and future therapeutic applications

Liver fibrosis is a chronic and progressive outcome of liver injury and continues to be a major contributor to liver morbidity and mortality. It is characterized by the excessive accumulation of extracellular matrix, resulting in the loss of normal liver architecture. Chronic liver injury also affects the availability of oxygen in the liver tissue, resulting in a hypoxic microenvironment. Among the major mediators of the hypoxic response, hypoxia-inducible factor-1α (HIF-1α) has been identified as a major regulator of fibrogenesis. The major experimental and clinical data have shown that the HIF pathway is closely linked to the activation of hepatic stellate cells, inflammation, pathological angiogenesis, and metabolic derangements in the fibrotic liver. These events are interlinked and result in the promotion of ongoing matrix accumulation and tissue remodeling. Recent studies have also indicated that the hypoxic pathways may cross-talk with ferroptosis and iron-mediated oxidative damage, providing new information on the mechanisms underlying the progression of fibrosis. This review aims to provide an overview of the current evidence on the role of HIF-1α in liver fibrosis and its connection between the major profibrotic pathways. We also provide information on the new therapeutic approaches targeting hypoxia signaling, including pharmacological inhibitors, von hippel-lindau (VHL) pathway modulation, and naturally derived compounds that have been reported to possess antifibrotic activity. A better understanding of the mechanisms driven by hypoxia may provide new information for the development of more accurate and stage-specific therapies for chronic liver diseases.

Emerging roles of mitophagy in liver fibrosis: Implications for therapy.

Contribution of p38 MAPK in liver fibrosis: An overview of mechanisms, signaling pathways, and therapeutic targets (Review)

Liver fibrosis is a progressive pathological state characterized by aberrant accumulation of extracellular matrix (ECM), predominantly mediated by activation of hepatic stellate cells (HSCs). If left untreated, this condition can progress to cirrhosis, liver failure, and even hepatocellular carcinoma. As a pivotal constituent of the mitogen-activated protein kinase (MAPK) superfamily, p38 MAPK orchestrates critical cellular processes, including proliferation, differentiation, and stress responses. The p38 MAPK signaling cascade has been identified as a central orchestrator of the pathogenic mechanisms underlying liver fibrosis, mediating key processes such as HSC activation, ECM remodeling, inflammation, oxidative stress, and apoptosis. Developing novel antifibrotic therapies hinges on a comprehensive elucidation of the functional roles and regulatory mechanisms governing p38 MAPK. The present review aims to provide an exhaustive synthesis of the mechanisms and signaling networks by which p38 MAPK contributes to liver fibrogenesis. Its roles in HSC transformation, interactions with other critical pathways (including NF-κB, TGF-β/Smad, JAK/STAT, and PI3K/Akt), and involvement in inflammatory and oxidative responses are explored. Furthermore, the therapeutic potential of targeting p38 MAPK is highlighted by preclinical evidence from pharmacological inhibitors, natural compounds, and traditional medicines that modulate this pathway to attenuate fibrosis. In conclusion, while p38 MAPK represents a promising therapeutic target for liver fibrosis, future research should focus on developing isoform-specific inhibitors, understanding context-dependent signaling outcomes, and designing combination therapies to enhance efficacy and minimize off-target effects. This synthesis aims to bridge current molecular insights with clinical translation, offering a roadmap for future antifibrotic drug development.

Cholesterol and p53 promote senescence and systemic fibrosis in metabolic dysfunction-associated steatohepatitis

Background & aims TP53 (p53) coordinates diverse cellular stress response programmes including pro-survival activities, senescence, and cell death. During tissue damage, p53 can shape both the local cellular response to injury, including the fibrotic response, and influence distal organ biology. Fibrosis in the liver is a major driver of hepatocellular carcinoma (HCC) risk within metabolic dysfunction-associated steatohepatitis (MASH). It is also an important determinant of dysfunction in multiple distal tissues including the kidneys, lungs, and heart. Despite significant clinical burden, our understanding of the molecular determinants of fibrotic MASH and its relationship to multiorgan fibrosis remain incomplete. Here, we investigate local and systemic effects of hepatocellular p53 activity and cholesterol during MASH development, with implications for disease prevention. Methods This study utilised a genetic model of stabilised p53, diet-induced MASH models with varying cholesterol compositions, and an in vitro obesogenic system to investigate p53 activity during liver disease development. Non-invasive imaging and histopathological analyses were employed to monitor p53 activity, MASH, and multiorgan fibrosis in vivo. Complementary approaches, including in vitro human multicomponent liver spheroids, cytokine arrays, and analyses of human MASH transcriptomic and proteomic datasets, were used to examine molecular drivers and patient relevance. Results Using an inducible mouse model of MDM2 E3 ubiquitin ligase deficiency to stabilise p53, we report that hepatocellular MDM2 E3 loss results in progressive fibrotic damage, robust hepatocellular expression of the p53 target gene CDKN1A/p21 (p21),and induces p21 and fibrosis in the kidneys of male mice in a sex-specific manner. In diet-induced MASH, we observe cholesterol and p53-dependent development of liver fibrosis, high expression of hepatocellular p21, and induction of p21 and fibrosis in the kidneys of male mice—reminiscent of features observed in MDM2 E3-deficient mice. We also observe fibrosis in the lungs and heart of male MASH mice. Both a cholesterol-free obesogenic diet and liver-specific loss of p53 mitigate hepatic fibrosis and systemic induction of p21 and fibrosis. Mechanistically, p53 induces hepatic expression of senescence-associated secretory phenotype (SASP) factors, including GDF15, in vivo. A human multicomponent LiverACE spheroid model showed a concordant trend towards increased GDF15 protein abundance under steatotic stress, while in humans, elevated circulating GDF15 levels in advanced MASH correlate with increased TNFRSF1A and EPHA2, circulating markers linked to kidney injury. Conclusions Our work identifies undue p53 activity within the liver as a driver of multiorgan fibrosis in a sex-specific manner, affecting male but not female mice. We implicate cholesterol in promoting this pro-fibrotic environment in vivo and highlight circulating factors that could identify at-risk patients for multiorgan fibrosis in MASH. IMPACT AND IMPLICATIONS P53 is a potent tumour suppressor that is frequently mutated or lost in HCC. Our findings suggest that dietary cholesterol promotes detrimental overactivation of p53 in MASH and facilitates fibrosis within the liver and distal organs. Further studies evaluating the efficacy of targeting hepatic p53 in combination with dietary or weight loss interventions could provide new treatment approaches for systemic fibrosis and MASH.