Piezo1/2 in fibrosis: Cell-type-specific roles, organ-specific pathogenesis, and therapeutic implications

Fibrosis is a pathological process affecting multiple organs, in which matrix stiffness-associated mechanotransduction plays a critical initiating and regulatory role. Piezo1/2 channels are key mechanosensors in fibrosis, with cell-type-specific causal roles supported by evidence ranging from association studies to genetic interventions. However, reported findings appear contradictory, with studies suggesting both pro-fibrotic and anti-fibrotic effects. This divergence is not merely biological noise but likely stems from critical differences in experimental models, methodological limitations, and the highly context-dependent nature of Piezo function (varying by cell type, tissue microenvironment, and disease stage). This review critically evaluates the evidence, highlighting methodological pitfalls (e.g., in vitro stiffness models, off‑target drug effects, genetic model caveats) that may underlie discrepancies. We provide a cell‑ and context‑resolved framework to guide future targeting of Piezo channels in anti‑fibrotic strategies.