Targeting Cellular Senescence: A New Therapeutic Axis in Chronic Liver Disease

Cellular senescence, a state of irreversible cell cycle arrest, is increasingly recognized as a key pathological driver of the progression of chronic liver diseases from metabolic dysfunction and fibrosis to hepatocellular carcinoma. While initially acting as a tumor-suppressive mechanism to eliminate damaged cells, the chronic accumulation of senescent cells creates a proinflammatory, profibrotic microenvironment through the senescence-associated secretory phenotype (SASP), thereby promoting tissue damage. This review examines the context-dependent mechanisms of cellular senescence across a range of chronic liver diseases, including metabolic, immune-mediated, viral, and malignant conditions. Building on these mechanisms, we critically assess the therapeutic landscape—from the selective clearance of senescent cells to novel strategies that modulate the senescence program—highlighting both their promise and current limitations. Despite the generally promising preclinical results, the clinical translation of senotherapies faces significant hurdles, including the heterogeneity of senescence, a lack of specific biomarkers, and potential off-target effects. Overcoming these challenges through emerging technologies will be crucial to harnessing senescence as a new therapeutic axis for chronic liver disease.