Uterine fibroid cells cultured on stiff substrates (~3 GPa) versus soft substrates (930 kPa) showed markedly elevated senescence markers p16 and p21, alongside fibrotic proteins fibronectin, PAI1, and α-SMA. The Src kinase inhibitor dasatinib — already FDA-approved as a senolytic — reduced both senescence and fibrosis markers while suppressing β-catenin activity, placing Src upstream in the signaling cascade. β-Catenin inhibitors ICG001 and PRI724 independently suppressed downstream targets CTGF and cyclin D1, confirming the pathway's centrality.
This work illuminates a self-reinforcing feedback loop that has been poorly characterized in fibroid biology: mechanical stiffness drives cellular senescence, senescent cells secrete profibrotic factors that further stiffen the extracellular matrix, and that stiffness perpetuates the cycle. The mechanosensing-to-senescence axis mirrors findings in liver fibrosis and pulmonary fibrosis research, but its mapping here to fibroid pathology is genuinely novel. Dasatinib's dual role as both a tyrosine kinase inhibitor and a clinically validated senolytic makes it an unusually translatable candidate — human trials of dasatinib plus quercetin for senescence-related conditions already exist, providing a potential regulatory pathway. Key limitations: this is in vitro cell culture work with no animal or human tissue validation of the therapeutic interventions, and the substrate stiffness values used (~3 GPa) substantially exceed physiological fibroid tissue stiffness (~20–50 kPa), which may amplify effect sizes artificially. Confirmatory in vivo studies are essential before clinical extrapolation. Overall: mechanistically instructive, with genuine therapeutic leverage points.