PIEZO1 promotes YAP/TEAD-dependent profibrotic signaling in POSTN-enriched lung fibroblast activation

Idiopathic pulmonary fibrosis (IPF) is driven by persistent fibroblast activation, excessive extracellular matrix (ECM) deposition, and progressive tissue stiffening, yet the mechanosensitive signaling programs that sustain fibrotic fibroblast states remain incompletely defined. Here, we investigated the association between a periostin (POSTN)-enriched fibrotic program and PIEZO1-dependent Yes-associated protein (YAP)/TEA domain transcription factor (TEAD) activation in IPF. Integrated analysis of public bulk lung transcriptomic datasets identified a reproducible POSTN-enriched ECM remodeling program in IPF lungs. Single-cell and donor-level pseudobulk analyses further showed that a PIEZO1/YAP activity-related signature was co-enriched in POSTN-positive fibrotic fibroblast and myofibroblast compartments. In bleomycin-induced pulmonary fibrosis, Postn upregulation, Piezo1 induction, and increased Yap nuclear localization were recapitulated in fibrotic lung regions. Verteporfin, used as a pharmacological inhibitor of Yap/TEAD-associated transcription, attenuated collagen deposition, hydroxyproline accumulation, profibrotic gene expression, and Yap target protein induction in vivo. In transforming growth factor-β1 (TGF-β1)-stimulated lung fibroblasts, verteporfin suppressed fibroblast migration, Yap nuclear localization, and profibrotic marker expression at non-cytotoxic concentrations. Knockdown of Piezo1 or Yap1 reduced TGF-β1-induced fibroblast activation, while Piezo1 knockdown decreased Yap nuclear localization and Yap/TEAD reporter activity. Active YAP partially restored profibrotic gene expression after Piezo1 knockdown, supporting Yap/TEAD as an important downstream effector of Piezo1. Collectively, these findings identify an association between a POSTN-enriched fibrotic fibroblast state and enhanced PIEZO1-YAP/TEAD signaling, while functional experiments support a role for PIEZO1-YAP/TEAD in fibroblast activation and fibrotic lung remodeling.