Piezo1/ITGB1 Synergizes With Ca²⁺/YAP Signaling to Propel Bladder Carcinoma Progression via a Stiffness-Dependent Positive Feedback Loop

Background: Emerging evidence implicates mechanotransduction pathways in modulating bladder carcinoma (BLCA) pathogenesis. However, the crosstalk between Piezo1 and integrin β1 (ITGB1) in extracellular matrix (ECM) stiffness-driven tumorigenesis remains a critical knowledge gap. This study systematically investigates the functional synergy of Piezo1/ITGB1 in orchestrating ECM biomechanical remodeling to fuel BLCA progression. Methods: Utilizing an integrative framework combining clinical histopathology, in vivo tumor models, multiomics profiling, molecular biology experiments, matrix stiffness quantification, calcium flux analysis, and YAP signaling interrogation, we dissected the mechanochemical interplay between Piezo1/ITGB1 activation and ECM dynamics. Results: Clinical and animal data revealed that Piezo1/ITGB1 coactivation was strongly correlated with ECM stiffness-induced BLCA proliferation and poor clinical prognosis. The coordinated expression of Piezo1/ITGB1 enhanced ECM interaction, organization, adhesion, and collagen binding. Crucially, Piezo1/ITGB1 overexpression promoted cancer development by suppressing apoptosis and enhancing proliferation. Mechanistically, ECM stiffness triggered Piezo1/ITGB1-dependent Ca²⁺ influx, which facilitated YAP nuclear translocation and subsequent upregulation of downstream targets CTGF, α-SMA, and COL1A1, thereby reinforcing collagen deposition and matrix stiffening. Conclusion: Our work uncovers a feedforward mechano-oncogenic axis wherein Piezo1/ITGB1 cooperativity converts ECM cues into sustained protumorigenic signaling through Ca²⁺/YAP-mediated transcriptional reprogramming. This paradigm redefines ECM stiffness not merely as a pathological consequence but as an active driver of BLCA progression, proposing precision targeting of the Piezo1/ITGB1 triad as a mechanotherapy strategy.