Objective To investigate the effect of Piezo1 activated by mechanical stress on KOA synovial fibrosis via ERK1/2 signaling pathway. Methods (1) Animal experiments: 25 SD rats were divided into blank group, exercise group, exercise +GsMTx4 group, exercise +PD98059 group, exercise +GsMTx4+PD98059 group, 5 in each group. After the modeling was completed, the serum and synovial tissue of rats were extracted and the collagen deposition was evaluated by Sirius scarlet staining and Masson staining. Western Blot and RT-qPCR were used to detect the expressions of Piezo1, ERK1/2, p-ERK1/2, α-SMA, TGF-β, Collagen I and TIMP-1, and the contents of IL-1β, IL-6 and TNF-α were detected by ELISA. (2) Cell experiment: the synovial cells were divided into five groups: blank group, pull group, pull +GsMTx4 group, pull +PD98059 group, pull +GsMTx4+PD98059 group. WB, RT-qPCR and other techniques were used to detect the above indexes in the molded cells. Results (1) Animal experiments: Mechanical stress increased Collagen deposition in synovial tissue of rats, and increased the protein and mRNA expressions of Piezo1, P-ERK /Erk, α-SMA, TGF-β, Collagen I and TIMP-1 of pathway-related and fibrosis-specific indicators (P< 0.05). The expression of Piezo1 was significantly down-regulated with both inhibitors (P< 0.05), but the ERK inhibitor (PD98059) had no significant effect on PIEZO1 expression. The content of serum inflammatory factors in exercise group was significantly higher than that in blank group (P < 0.05), and the improvement was obvious after the use of inhibitors (P< 0.05). (2) Cell experiment: WB and RT-qPCR results showed the same trend as animal experiments. Conclusion The Piezo1 ion channel can sense mechanical stress and activate the ERK1/2 pathway to mediate knee synovial fibrosis.