Redefining senescence through hepatocyte fate changes in liver diseases

Hepatocyte senescence is increasingly recognized as a key contributor to liver pathophysiology. While traditionally viewed as a state of permanent growth arrest, hepatocyte senescence is now understood to be more dynamic and potentially reversible, particularly during liver repair. In this opinion article, we propose reframing senescence as a continuum rather than a terminal fate. We focus on early stress-responsive states, especially those marked by p21 expression, which may be adaptive or pro-regenerative depending on the context. We highlight the roles of p21-associated secretory phenotypes (PASPs), senescence-associated secretory phenotypes (SASPs), epithelial plasticity, and partial epithelial-to-mesenchymal transition (EMT) in modulating hepatocyte behavior, immune surveillance, and cancer risk. Viewing hepatocyte senescence as a trajectory opens new opportunities for context-specific and temporally targeted therapeutic strategies in liver disease.