Context-dependent duality of senescent cells in liver fibrosis

Abstract

Liver fibrosis, marked by excessive deposition of extracellular matrix (ECM), is a critical precursor to cirrhosis, liver failure, and hepatocellular carcinoma. Accumulating evidence highlights that cellular senescence, characterized by stable cell-cycle arrest and senescence-associated secretory phenotypes (SASPs), is a key regulator of the fibrotic process. This review systematically dissects the context-dependent roles of senescent cells in liver fibrosis, with a focus on hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), Kupffer cells, and natural killer (NK) cells. Distinct populations of senescent cells emerge sequentially during different stages of fibrosis, exhibiting divergent kinetics and functional effects. The SASP, a dynamic cocktail composed of cytokines, chemokines, and proteases, remodels the intrahepatic microenvironment through immune cell recruitment, regulation of cell function, and modulation of ECM turnover. These effects vary depending on their molecular composition and disease context. Furthermore, we discuss emerging senescence-targeted therapeutic strategies to restore liver homeostasis. In-depth understanding of the cell-type and stage-specific roles of senescence in fibrosis provides a molecular foundation for translating senescence-targeted strategies into clinical precision antifibrotic therapies.