Hepatic fibrosis, driven by chronic liver injury, results from complex interactions between hepatocytes and hepatic stellate cells (HSCs). In response to hepatocyte damage, activated HSCs undergo transdifferentiation into myofibroblast-like cells, contributing to the accumulation of extracellular matrix (ECM) components and the progression of fibrosis. This review explores the intricate bidirectional crosstalk between hepatocytes and HSCs, focusing on the molecular mechanisms underlying their interactions during liver fibrosis. Hepatocytes, upon injury, release inflammatory mediators, reactive oxygen species (ROS), and exosomes, which activate HSCs and promote fibrotic progression. Conversely, activated HSCs exacerbate hepatocyte dysfunction through cytokine release, ECM remodeling, and mechanical stress. Key signaling pathways, including transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and oxidative stress mechanisms, are central to these processes. The review also discusses current challenges in targeting hepatic fibrosis and proposes future research directions, including the use of multi-omics technologies to unravel the dynamic spatiotemporal interactions between hepatocytes and HSCs. Understanding this intricate regulatory network will be crucial for the development of novel therapeutic strategies to reverse liver fibrosis and improve patient outcomes.
Niu et al. (2026) studied this question.