Piezo1-centered mechanotransduction in knee osteoarthritis: multicompartment mechano-inflammatory networks and therapeutic opportunities

Abstract Knee osteoarthritis (KOA) is increasingly recognized as a whole-joint mechano-inflammatory disorder in which abnormal loading, tissue remodeling, and inflammatory sensitization reinforce one another. Piezo1 is a context-dependent mechanotransduction hub that links mechanical cues to Ca 2+ -dependent inflammatory, catabolic, cell-death, and organelle-stress responses. This focused review, supported by a structured search of PubMed, Web of Science, and China National Knowledge Infrastructure from database inception through June 2, 2026, synthesizes evidence across articular cartilage, synovium, subchondral bone, osteophyte formation, and the pain-related microenvironment. Dysregulated Piezo1-associated signaling has been implicated in extracellular matrix degradation, chondrocyte dysfunction, cell-fate imbalance, and organelle stress. Importantly, Piezo1 is not uniformly pathogenic: excessive activation can aggravate injury in mature chondrocytes and other joint cells, whereas Piezo1 activity may support reparative responses in selected progenitor-cell populations. Preclinical studies have investigated whether traditional Chinese medicine-related interventions alter components of the Piezo1-associated mechano-inflammatory network, although direct target engagement and causal validation remain limited. Artemisinin, wogonin, Shengyu Decoction, and Gubi Zhitong Formula have been associated with changes in distinct molecular modules, whereas evidence linking acupuncture and acupotomy to Piezo1 remains limited to heterogeneous preclinical models and does not establish direct or Piezo1-specific therapeutic mechanisms. However, translation remains limited by heterogeneous models, insufficient compartment- and cell-specific validation, incomplete exposure and target-engagement data, and inconsistent procedural standards. Future studies should integrate local and reversible intervention strategies, rigorous quality control, standardized procedural and stimulation parameters, and cell-specific causal validation. Piezo1 may therefore serve as a stratifiable and testable organizing axis for developing more precise KOA interventions.