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.