Mechanical Activation of Piezo1 Drives Osteoarthritis Through Kdm5c‐Mediated Epigenetic Silencing

ABSTRACT Mechanical stress is the most important factor affecting the progression of osteoarthritis (OA), but the mechanism linking mechanical stress to transcriptional repression remains elusive. Here, the study finds that mechanical stress induced epigenetic changes that can serve as therapeutic targets for osteoarthritis. By using Piezo1 conditional knockout ( Col2a1 CreERT ; Piezo1 flox/flox ) mice, it was found that Piezo1 activation by excessive mechanical stress can trigger chromatin remodeling via cytoskeletal force transmission, promoting the histone demethylase Kdm5c‐mediated epigenetic silencing. Kdm5c in turn erases H3K4me3 marks from promoters of cartilage‐anabolic genes Col2a1 and Runx3 , silencing their expression. Genetic ablation of Kdm5c rescues mechanical stress‐induced cartilage degradation. Through drug repurposing, the study identifies telmisartan as a direct Kdm5c inhibitor that blocks this pathway and demonstrates disease‐modifying efficacy in mouse OA models and human cartilage explants. These results establish the Piezo1–Kdm5c axis as a fundamental driver of OA and position telmisartan as a mechano‐epigenetic therapy with immediate translational potential.