The study investigates the role of Piezo1 in promoting skin fibrosis through a positive feedback loop involving mechanical stiffness, Wnt2/Wnt11 signaling, and CCL24 secretion. Piezo1 is upregulated in fibrotic human and mouse skin tissues, particularly in myofibroblasts. In vitro experiments show that increased substrate stiffness upregulates Piezo1 expression and promotes dermal fibroblast (HDF) activation. Piezo1 acts through the Wnt2/Wnt11 pathway to induce the secretion of CCL24, a cytokine associated with fibrotic disorders. AAV-mediated Piezo1 knockdown ameliorates skin fibrosis progression and stiffness in mice. The findings suggest that targeting Piezo1 can break the positive feedback loop between mechanotransduction and aberrant tissue mechanics in skin fibrosis.The study investigates the role of Piezo1 in promoting skin fibrosis through a positive feedback loop involving mechanical stiffness, Wnt2/Wnt11 signaling, and CCL24 secretion. Piezo1 is upregulated in fibrotic human and mouse skin tissues, particularly in myofibroblasts. In vitro experiments show that increased substrate stiffness upregulates Piezo1 expression and promotes dermal fibroblast (HDF) activation. Piezo1 acts through the Wnt2/Wnt11 pathway to induce the secretion of CCL24, a cytokine associated with fibrotic disorders. AAV-mediated Piezo1 knockdown ameliorates skin fibrosis progression and stiffness in mice. The findings suggest that targeting Piezo1 can break the positive feedback loop between mechanotransduction and aberrant tissue mechanics in skin fibrosis.