Context-dependent STAT3 signaling in liver fibrosis.

Decoding fibroblast activation: Transcriptional networks in hepatic stellate cells and across fibrotic organs (Review)

Fibrosis is a progressive pathological process characterized by excessive extracellular matrix (ECM) deposition and structural remodeling that ultimately leads to organ dysfunction. In organs such as the liver, lung, heart and kidney, sustained activation of fibroblasts and their differentiation into myofibroblasts are key drivers of fibrotic progression. Growing evidence suggests that these cellular transitions are regulated by intricate transcriptional networks that integrate inflammatory, metabolic and mechanical signals. Liver fibrosis provides a well-established framework for studying the transcriptional regulation of fibroblast activation, largely driven by the differentiation of hepatic stellate cells (HSCs) into collagen-secreting myofibroblasts. Various transcription factors coordinate major signaling pathways to regulate fibroblast proliferation, ECM production and cell survival. These transcriptional programs not only sustain fibrogenesis but also influence whether fibrotic responses resolve or progress to chronic tissue scarring. In the present review, current advances in understanding transcriptional regulatory networks governing fibroblast activation were summarized, with a primary focus on HSCs while highlighting shared mechanisms across multiple fibrotic organs. Emerging therapeutic strategies targeting transcription factors and their upstream regulatory pathways were further discussed. A deeper understanding of these transcriptional circuits may facilitate the development of novel antifibrotic therapies and enhance strategies for resolving fibrosis in various organs.

Epigenetic Regulation of Liver Fibrosis: Mechanisms and Therapeutic Implications

Liver fibrosis is a common consequence of chronic liver injury and a major contributor to liver‐related mortality. Persistent hepatocellular injury promotes fibrosis initiation and progression through excessive extracellular matrix deposition. Hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transition from a quiescent state to an activated myofibroblast‐like phenotype in response to profibrotic stimuli such as transforming growth factor‐beta. This transition is accompanied by transcriptional and epigenetic reprogramming involving DNA methylation, histone modifications, and regulation by non‐coding RNAs. Treating the underlying cause of liver disease, such as promoting weight loss in metabolic dysfunction‐associated steatohepatitis or eradicating viral hepatitis, remains the principal strategy for slowing or potentially reversing fibrosis. Despite substantial advances in understanding the cellular and molecular basis of liver fibrosis and HSC activation, most mechanism‐based therapeutic approaches have not yet demonstrated clinical efficacy. Further translational and clinical studies are therefore required. Recent advances in molecular biology have highlighted the potential relevance of epigenetic modifications to the diagnosis, treatment, and prognosis of chronic liver disease. In this review, we summarize the principal epigenetic changes involved in HSC activation, and initiation/progression of liver fibrosis. We also discuss recent interventions designed to modulate these epigenetic changes and evaluate their therapeutic potential in experimental models of liver fibrosis.

Epigenetic Regulation in Liver Fibrosis: Focus on the Chromatin Accessibility Landscape.

Liver fibrosis is a key pathological process in the progression of chronic liver disease to cirrhosis and hepatocellular carcinoma, with core features including hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition. Nonetheless, the precise spatiotemporal regulatory mechanisms of its gene expression have not been fully clarified. Interestingly, chromatin accessibility, as a core level of epigenetic regulation, directly determines the expression "switch" of fibrosis-related genes by dynamically altering the chromatin open state, which is closely related to key pathological processes such as HSCs activation, hepatocyte injury, and immune cell infiltration. Chromatin accessibility is coordinately modulated by histone modifications, ATP-dependent chromatin remodelers, CpG methylation, as well as enhancers, super-enhancers, and transcription factors, which together constitute a multilayered epigenetic network. Key regulatory mediators, including histone deacetylases (HDACs), histone acetyltransferase p300 (p300), bromodomain-containing protein 4 (BRD4), DNA methyltransferases (DNMTs), and methyl-CpG-binding protein 2 (MeCP2), have emerged as promising therapeutic candidates. Relevant inhibitors or interventions can inhibit HSCs activation and ECM deposition by reversing abnormal chromatin accessibility. An in-depth study of the regulatory network of chromatin accessibility may provide new perspectives on the pathogenesis of liver fibrosis and lay a theoretical foundation for the development of novel precision-targeted drugs.

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.

Hypoxia-inducible factor-1 (HIF-1) in the molecular mechanisms of liver fibrosis: research progress on its role and therapeutic strategies.

Kinase regulation of miRNA networks in cardiometabolic disease: emerging pathways to precision therapy