SERPINE1 (PAI-1) Regulation in Mechanotransduction-Associated Cellular Senescence.

Cellular senescence is a complex biological process characterized by irreversible cell-cycle arrest and acquisition of the senescence-associated secretory phenotype (SASP). Beyond biochemical stress, increasing evidence indicates that mechanical cues from the extracellular microenvironment contribute to the regulation of senescence; however, the molecular mechanisms linking mechanotransduction to senescent phenotypes remain incompletely understood. SERPINE1 (plasminogen activator inhibitor-1, PAI-1) has emerged as a key mechanosensitive effector induced downstream of mechanotransduction signaling pathways. In this review, we discuss SERPINE1 as both a hallmark of cellular senescence and a functional mediator linking mechanotransduction to senescence-associated processes. Once induced, SERPINE1 contributes to cell-cycle arrest and extracellular matrix (ECM) remodeling by inhibiting plasmin-dependent proteolysis. The resulting ECM accumulation and matrix stiffening further enhance integrin-dependent mechanotransduction, promoting further SERPINE1 expression and establishing a self-reinforcing mechanobiological feedback loop. SERPINE1 also contributes to senescence-associated inflammatory signaling, which may further support the maintenance of the senescent phenotype. Together, these findings identify SERPINE1 as a mechanistic link between mechanotransduction, ECM remodeling, and cellular senescence. Pharmacological studies using PAI-1 inhibitors further support the biological importance of this pathway and suggest that SERPINE1 may represent a potential therapeutic target for senescence-associated fibrotic diseases.