A role for ferroptosis in articular cartilage destruction associated with rheumatoid arthritis (RA) has not been identified. We previously reported transient receptor potential melastatin 7 (TRPM7) expression was correlated with RA cartilage destruction. Herein, we further characterized a role for TRPM7 in chondrocyte ferroptosis. The expression of TRPM7 was found to be elevated in articular chondrocytes derived from adjuvant arthritis (AA) rats, human RA patients, and cultured chondrocytes treated with the ferroptosis inducer, erastin. TRPM7 knockdown or pharmacological inhibition protected primary rat articular chondrocytes and human chondrocytes (C28/I2 cells) from ferroptosis. Moreover, TRPM7 channel activity was demonstrated to contribute to chondrocyte ferroptosis by elevation of intracellular Ca²⁺. Mechanistically, the PKCα-NOX4 axis was found to respond to stimulation with erastin, which resulted in TRPM7-mediated chondrocyte ferroptosis. Meanwhile, PKCα was shown to directly bind to NOX4, which could be reduced by TRPM7 channel inhibition. Adeno-associated virus 9-mediated TRPM7 silencing or TRPM7 blockade with 2-APB alleviated articular cartilage destruction in AA rats and inhibited chondrocyte ferroptosis. Collectively, both genetic and pharmacological inhibitions of TRPM7 attenuated articular cartilage damage and chondrocyte ferroptosis via the PKCα-NOX4 axis, suggesting that TRPM7-mediated chondrocyte ferroptosis is a promising target for the prevention and treatment of RA.

铁死亡在与类风湿性关节炎（RA）相关的关节软骨破坏中的作用尚未确定。我们之前报道过瞬态受体电位褪黑激素 7 (TRPM7) 表达与 RA 软骨破坏相关。在此，我们进一步表征了 TRPM7 在软骨细胞铁死亡中的作用。研究发现，来自佐剂性关节炎 (AA) 大鼠、人类 RA 患者以及经铁死亡诱导剂erastin 处理的培养软骨细胞的关节软骨细胞中，TRPM7 的表达升高。TRPM7 敲低或药物抑制可保护原代大鼠关节软骨细胞和人软骨细胞（C28/I2 细胞）免于铁死亡。^{此外，TRPM7 通道活性被证明可通过细胞内 Ca 2+}升高导致软骨细胞铁死亡。从机制上讲，PKCα-NOX4 轴被发现会对erastin 的刺激做出反应，从而导致 TRPM7 介导的软骨细胞铁死亡。同时，PKCα 被证明可以直接与 NOX4 结合，并且可以通过抑制 TRPM7 通道来减少这种结合。腺相关病毒 9 介导的 TRPM7 沉默或用 2-APB 阻断 TRPM7 可减轻 AA 大鼠的关节软骨破坏并抑制软骨细胞铁死亡。总的来说，TRPM7 的遗传和药理学抑制可通过 PKCα-NOX4 轴减轻关节软骨损伤和软骨细胞铁死亡，表明 TRPM7 介导的软骨细胞铁死亡是预防和治疗 RA 的有希望的靶点。