Piezo1 at the crossroads: Mediating inflammation and mechanical stress in joint disorders.

Piezo1 is a mechanosensitive ion channel, which plays a pivotal role in translating mechanical stress into cellular signaling, thereby influencing inflammatory responses and tissue remodeling in joint disorders. Current evidences showed that Piezo1 functions as a mechanotransducer and amplifier of inflammation across joint disorders including osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and intervertebral disc degeneration (IVDD). In OA, Piezo1 mediates chondrocyte apoptosis and matrix degradation via calcium influx, NF-κB/MAPK activation, and ferroptosis, forming a feedback loop with IL-1α to exacerbate inflammation. In AS, Piezo1 drives pathological new bone formation through CaMKII signaling, synergizing with TNF-α/IL-17A to perpetuate entheseal inflammation. In IVDD, Piezo1-induced calcium dysregulation triggers mitochondrial dysfunction, NLRP3 inflammasome activation, and YAP/TAZ-mediated extracellular matrix (ECM) degradation, creating a self-amplifying cycle of mechanical stress and inflammation. Targeting Piezo1 emerges as a potential therapeutic strategy, with preclinical studies demonstrating inhibition of Piezo1 alleviates disease progression by disrupting mechanotransduction-inflammation crosstalk. However, challenges remain in achieving tissue-specific modulation. Future research should focus on elucidating Piezo1's context and developing precision therapeutics to restore mechanobiological balance in joint diseases.