PAI-1 Links Mechanical Stress to Cellular Aging in a Self-Reinforcing Loop

As tissues age, their mechanical environment changes — matrices stiffen, cells experience altered tensile forces, and the biophysical cues governing gene expression shift substantially. This comprehensive review examines how SERPINE1 (plasminogen activator inhibitor-1, PAI-1) functions as a molecular hub connecting these mechanical changes to the hallmarks of cellular senescence, offering a unified mechanobiological framework for understanding age-related tissue dysfunction.

The authors systematically map the transcriptional regulation of SERPINE1 downstream of mechanotransduction. Two core signaling axes are highlighted. First, the YAP/TAZ–TEAD axis: on stiff matrices, integrin clustering activates FAK-Src and RhoA-ROCK signaling, increasing actomyosin contractility, promoting nuclear accumulation of YAP/TAZ, and driving TEAD-dependent SERPINE1 transcription. Knockdown of YAP/TAZ in lung fibroblasts attenuates stiffness-induced SERPINE1 expression, confirming this pathway's mechanistic importance. Second, the TGF-β/SMAD pathway: mechanical forces transmitted through αv-integrins deform the latency-associated peptide (LAP) anchored to the ECM via LTBP-1, releasing active TGF-β1 without proteolytic cleavage. This activates SMAD2/3-SMAD4 complexes that directly transactivate the SERPINE1 promoter. Additional context-dependent transcription factors — AP-1, NF-κB, HIF-1α, and p53 — integrate mechanotransduction with inflammatory, oxidative, and genotoxic stress signals to further modulate SERPINE1 expression.

Once induced, SERPINE1 inhibits tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, reducing plasmin generation and thereby limiting plasmin-dependent ECM proteolysis. The resulting ECM accumulation and matrix stiffening create a stiffer mechanical microenvironment that feeds back to enhance integrin-dependent mechanotransduction — establishing a self-reinforcing mechanobiological feedback loop. This loop promotes further SERPINE1 expression and progressive ECM remodeling characteristic of fibrosis.

SERPINE1's role in cellular senescence is multifaceted. It contributes to cell-cycle arrest, is a recognized component of the senescence-associated secretory phenotype (SASP), and participates in pro-inflammatory signaling that sustains the senescent state. The review argues that SERPINE1-driven ECM stiffening is not merely a downstream consequence of senescence but an active reinforcing mechanism. Pharmacological inhibition of PAI-1 has shown promise in preclinical fibrotic disease models, supporting SERPINE1 as a potentially druggable node in this pathway.

The review draws primarily from fibroblast and epithelial cell models, where mechanistic evidence is strongest, while noting broader relevance across mechanically responsive tissues including vascular and pulmonary systems. The authors acknowledge that causal directionality across all proposed feedback steps requires further experimental validation, and that context-specific ECM composition, crosslinking, and cellular tension may modulate the magnitude of these effects.