Mechanical stiffness promotes skin fibrosis through a positive feedback loop involving the mechanosensitive ion channel Piezo1 and the Wnt2/Wnt11-CCL24 pathway. In fibrotic skin, Piezo1 is upregulated in myofibroblasts, and its expression is increased under higher matrix stiffness. Piezo1 activates the Wnt2/Wnt11 pathway, leading to the secretion of CCL24, a chemokine associated with fibrotic disorders. This pathway amplifies fibroblast activation, increasing ECM production and further stiffening the tissue, thus perpetuating the fibrotic process. AAV-mediated Piezo1 knockdown in mice reduces skin fibrosis and stiffness, indicating that targeting Piezo1 could break this feedback loop. The study highlights the role of Piezo1 in linking mechanical signals to fibroblast activation and fibrosis progression, suggesting that modulating Piezo1 could be a therapeutic strategy for skin fibrosis. The findings provide insights into the molecular mechanisms underlying skin fibrosis and suggest potential targets for intervention.Mechanical stiffness promotes skin fibrosis through a positive feedback loop involving the mechanosensitive ion channel Piezo1 and the Wnt2/Wnt11-CCL24 pathway. In fibrotic skin, Piezo1 is upregulated in myofibroblasts, and its expression is increased under higher matrix stiffness. Piezo1 activates the Wnt2/Wnt11 pathway, leading to the secretion of CCL24, a chemokine associated with fibrotic disorders. This pathway amplifies fibroblast activation, increasing ECM production and further stiffening the tissue, thus perpetuating the fibrotic process. AAV-mediated Piezo1 knockdown in mice reduces skin fibrosis and stiffness, indicating that targeting Piezo1 could break this feedback loop. The study highlights the role of Piezo1 in linking mechanical signals to fibroblast activation and fibrosis progression, suggesting that modulating Piezo1 could be a therapeutic strategy for skin fibrosis. The findings provide insights into the molecular mechanisms underlying skin fibrosis and suggest potential targets for intervention.