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

• Published in: The international journal of biochemistry & cell biology 2024-09, Vol.174, p.106618, Article 106618
• Main Authors: Hao, Wenjuan, Zhu, Rendi, Zhang, Hailin, Chen, Yong, Li, Shufang, Zhou, Fuli, Hu, Wei, Zhou, Renpeng
• Format: Article
• Language: English
• Subjects: 1-Naphthylamine - analogs & derivatives; 1-Naphthylamine - pharmacology; Animals; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrocytes - pathology; Ferroptosis; Ferroptosis - drug effects; Heme Oxygenase (Decyclizing); Heme Oxygenase-1 - metabolism; HO-1; Humans; Male; NS8593; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Rheumatoid arthritis; Signal Transduction - drug effects; TRPM Cation Channels - antagonists & inhibitors; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism; TRPM7
• ISSN: 1357-2725; 1878-5875; 1878-5875
• DOI: 10.1016/j.biocel.2024.106618

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.