The multifaceted roles of cellular senescence in liver pathophysiology: from tissue repair to tumor progression.

Abstract

Cellular senescence is a stress-response program that coordinates cell-autonomous growth arrest and non-cell autonomous remodeling of the tissue environment. Initially defined through its role in aging and tumor suppression, senescence is now recognized as a highly complex program shaped by cell-intrinsic and environmental factors. This complexity places senescence as a broad stress response mechanism operating at the intersection of metabolic dysfunction, chronic inflammation and tissue repair. Given its constant exposure to metabolic, inflammatory and toxic stress alongside its high regenerative demands, the liver is particularly prone to engage senescence as a protective mechanism to maintain tissue integrity. In this context, senescence exerts dual and often opposing effects. This review discusses the multifaceted roles of senescence along the liver disease trajectory, from its early protective functions in tissue repair to its later pathologic contributions to chronic liver disease and tumor progression, underscoring how cell type, stage of senescence program, disease stage and microenvironmental cues shape these divergent outcomes. We highlight the potential of emerging therapeutic interventions that modulate senescence, including pro-senescence, senolytic, senomorphic, and immune-modulating strategies. Advancing our understanding of the multifaceted roles of cellular senescence will be essential to translate this knowledge into therapies that selectively modulate senescent cell states, harnessing their beneficial effects while limiting their detrimental roles in chronic liver disease and cancer.