NS8593 inhibits chondrocyte ferroptosis and alleviates cartilage injury in rat adjuvant arthritis through TRPM7 / HO-1 pathway

Ferroptosis is an emerging target in rheumatoid arthritis (RA). We previously reported that transient receptor potential melastatin 7 (TRPM7) expression is correlated with RA cartilage destruction and demonstrated that TRPM7 mediates ferroptosis in chondrocytes. Here, we further determined the role and mechanism of (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593), a TRPM7 inhibitor, in chondrocyte ferroptosis of RA. We established in vitro models of ferroptosis in human chondrocytes (C28/I2 cells) by using ferroptosis inducer Erastin. The results showed that NS8593 could protect C28/I2 cells from ferroptosis by inhibiting TRPM7 channel, which was manifested by restoring cell viability, reducing cytotoxicity, affecting the expression of ferroptosis marker protein, and restoring redox balance to alleviate Erastin-induced oxidative stress injury. Mechanistically, the Heme oxygenase-1 (HO-1) axis responded to Erastin stimulation, which resulted in TRPM7-mediated chondrocyte ferroptosis，NS8593 could reduce the expression of HO-1 by inhibiting TRPM7 channel. Moreover, NS8593 alleviated articular cartilage destruction and inhibited chondrocyte ferroptosis in AA rats. In conclusion, NS8593 mitigated articular cartilage damage and chondrocyte ferroptosis through the TRPM7/HO-1 pathway, suggesting that NS8593 may be a potential novel drug for the treatment of RA.