Piezo1 accelerates osteoarthritis progression via promotion of HBB-dependent oxidative phosphorylation.

The mechanosensitive ion channel Piezo1 serves as a key regulator of osteoarthritis (OA) progression, but the underlying mechanism remains largely unknown. In the present study, Piezo1 was found to be upregulated in the articular cartilage of mice with post-traumatic (PT), caused by destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT) surgery, or obesity-induced OA, but not in age-related OA. This elevated Piezo1 expression triggered a signaling cascade via the KDM6B/KLF1 axis, leading to increased expression of hemoglobin subunit beta (HBB) in chondrocytes. The upregulation of HBB initially enhanced mitochondrial oxidative phosphorylation (OXPHOS), but subsequently impaired mitochondrial function owing to excessive reactive oxygen species (ROS) production, thereby driving chondrocytes an energy metabolism shift from OXPHOS to glycolysis to meet the energy requirements. Notably, intra-articular injection of cartilage-targeting nanoparticles (CAP-PEI) loaded with siRNA against either Piezo1 or HBB effectively restored mitochondrial OXPHOS capacity and attenuated OA progression in mice. Together, these results demonstrate that Piezo1 exacerbates PT and obesity-induced OA by upregulating HBB through the KDM6B/KLF1 pathway, highlighting the therapeutic potential of targeting this metabolic axis.