Modulating hepatic stellate cell senescence: A promising therapeutic strategy for liver fibrosis

Fibrosis is characterized by the abnormal deposition of extracellular matrix (ECM) components in liver tissue following chronic liver injury, ultimately leading to hepatic cirrhosis. Following liver damage, hepatic stellate cells (HSCs) undergo transition from a quiescent to an activated phenotype which differentiate into proliferative, fibrogenic, and contractile myofibroblasts. The activated HSCs act as the primary source of collagen in the injured liver, promoting scar formation and fibrogenesis while reducing ECM degradation. Therefore, potential therapeutic strategies for liver fibrosis include inhibiting HSC activation, proliferation, and function, as well as promoting their clearance through autophagy, pro-apoptotic agents, and senescence inducers. In recent years, the induction of HSC senescence has emerged as a promising therapeutic approach to halt fibrosis progression. This review provided a comprehensive analysis of the fundamental role of the senescence-associated secretory phenotype and its regulatory pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes, Notch signaling, nuclear factor kappa B, and mechanistic target of rapamycin complexes. This review also discussed each of these pathways in terms of their influence on the senescence behaviour of HSCs and their interactions within the fibrotic hepatic microenvironment. Recent advancements in identifying senescence markers, such as p21, β-galactosidase, interleukin-6, and urokinase plasminogen activator receptor, offer promising opportunities for targeted therapeutic interventions. Consequently, the strategic targeting of HSC senescence emerges as a compelling therapeutic approach for liver fibrosis, with the potential not only to halt disease progression but also to promote essential tissue remodeling processes.