Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
Int J Biochem Cell Biol. 2024 Sep;174:106618. doi: 10.1016/j.biocel.2024.106618. Epub 2024 Jul 23.
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.
铁死亡是类风湿关节炎（RA）的一个新兴靶点。我们之前报道过瞬时受体电位阳离子通道亚家族 M 成员 7（TRPM7）的表达与 RA 软骨破坏有关，并证实 TRPM7 介导软骨细胞中的铁死亡。在这里，我们进一步确定了 TRPM7 抑制剂（R）-N-（苯并咪唑-2-基）-1,2,3,4-四氢-1-萘胺（NS8593）在 RA 软骨细胞铁死亡中的作用和机制。我们通过使用铁死亡诱导剂 Erastin 在人软骨细胞（C28/I2 细胞）中建立了体外铁死亡模型。结果表明，NS8593 通过抑制 TRPM7 通道来保护 C28/I2 细胞免受铁死亡，这表现为恢复细胞活力、降低细胞毒性、影响铁死亡标志物蛋白的表达以及恢复氧化还原平衡以减轻 Erastin 诱导的氧化应激损伤。在机制上，血红素加氧酶-1（HO-1）轴对 Erastin 刺激作出反应，导致 TRPM7 介导的软骨细胞铁死亡，NS8593 通过抑制 TRPM7 通道可以降低 HO-1 的表达。此外，NS8593 减轻了 AA 大鼠的关节软骨破坏并抑制了软骨细胞铁死亡。总之，NS8593 通过 TRPM7/HO-1 通路减轻关节软骨损伤和软骨细胞铁死亡，表明 NS8593 可能是治疗 RA 的一种有潜力的新型药物。
