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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\u20101, PAI\u20101) 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\u2010associated processes. Once induced, SERPINE1 contributes to cell\u2010cycle arrest and extracellular matrix (ECM) remodeling by inhibiting plasmin\u2010dependent proteolysis. The resulting ECM accumulation and matrix stiffening further enhance integrin\u2010dependent mechanotransduction, promoting further SERPINE1 expression and establishing a self\u2010reinforcing mechanobiological feedback loop. SERPINE1 also contributes to senescence\u2010associated 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\u20101 inhibitors further support the biological importance of this pathway and suggest that SERPINE1 may represent a potential therapeutic target for senescence\u2010associated fibrotic diseases.<\/jats:p>","DOI":"10.1002\/jcb.70123","type":"journal-article","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:43:51Z","timestamp":1789922631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SERPINE1 (PAI\u20101) Regulation in Mechanotransduction\u2010Associated Cellular Senescence"],"prefix":"10.1002","volume":"127","author":[{"given":"Intan Chairun","family":"Nisa","sequence":"first","affiliation":[{"name":"Division of Bioengineering, Graduate School of Engineering Science University of Osaka Toyonaka Japan"},{"name":"Biotechnology Study Program Department of Applied Science, Faculty of Mathematics and Natural Sciences, Universitas Negeri Malang Malang 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