Effects and Therapeutic Strategies of Intra-Hepatic Cellular Senescence and Regeneration

The liver constitutes a vital organ characterized by remarkable regenerative capacity, wherein intra-hepatic cellular senescence and regeneration exert pivotal regulatory functions in maintaining hepatic homeostasis and in developing therapeutic interventions for liver diseases. Intra-hepatic cellular aging is typically characterized by diminished proliferative capacity, genomic instability, mitochondrial dysfunction, and exacerbated inflammatory responses, all of which contribute to hepatic functional impairment and the pathogenesis of associated diseases. Liver regeneration depends upon the proliferation and differentiation of hepatocytes—processes stringently regulated by diverse signaling pathways and microenvironmental factors. Notably, the relationship between hepatocyte aging and regeneration embodies a fundamental paradox: whereas acute, transient senescence may facilitate tissue repair through the senescence-associated secretory phenotype (SASP), chronic accumulation of senescent cells disrupts the hepatic microenvironment and suppresses regenerative capacity. This duality necessitates nuanced therapeutic strategies capable of distinguishing between beneficial and detrimental senescent cell populations. Interventions targeting cellular senescence, encompassing small-molecule anti-aging compounds, gene therapy, and stem-cell-based approaches, may represent promising therapeutic modalities for future liver disease management. This review reviews the molecular mechanisms underlying hepatocyte aging and regeneration, critically examines the contradictory roles of senescence in hepatic repair, and explores strategies that selectively target pathological senescence to promote liver regeneration. These insights may provide novel perspectives for the prevention and treatment of liver diseases.