Hyperglycaemia-induced ferroptosis is a significant contributor to kidney dysfunction in diabetic nephropathy (DN) patients. In addition, targeting ferroptosis has clinical implications for the treatment of DN. However, effective therapeutic targets for ferroptosis have not been identified. In this study, we aimed to explore the precise role of protein arginine methyltransferase 6 (PRMT6) in regulating ferroptosis in DN. In the present study, we utilized a mouse DN model consisting of both wild-type and PRMT6-knockout (PRMT6^−/−) mice. Transcriptomic and lipidomic analyses, along with various molecular biological methodologies, were used to determine the potential mechanism by which PRMT6 regulates ferroptosis in DN. Our results indicate that PRMT6 downregulation participates in kidney dysfunction and renal cell death via the modulation of ferroptosis in DN. Moreover, PRMT6 reduction induced lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 1 (ACSL1) expression, ultimately contributing to ferroptosis. Furthermore, we investigated the molecular mechanism by which PRMT6 interacts with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ACSL1 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. Furthermore, we observed that PRMT6 and STAT1 synergistically regulate ACSL1 transcription to mediate ferroptosis in hyperglycaemic cells. Our study demonstrated that PRMT6 and STAT1 comodulate ACSL1 transcription to induce the production of phospholipid-polyunsaturated fatty acids (PL-PUFAs), thus participating in ferroptosis in DN. These findings suggest that the PRMT6/STAT1/ACSL1 axis is a new therapeutic target for the prevention and treatment of DN.

高血糖诱导的铁死亡是糖尿病肾病 （DN） 患者肾功能障碍的重要因素。此外，靶向铁死亡对 DN 的治疗具有临床意义。然而，尚未确定铁死亡的有效治疗靶点。在这项研究中，我们旨在探讨蛋白精氨酸甲基转移酶 6 （PRMT6） 在调节 DN 铁死亡中的确切作用。在本研究中，我们利用了由野生型和 PRMT6 敲除 （PRMT6 ^−/−） 小鼠组成的小鼠 DN 模型。转录组学和脂质组学分析以及各种分子生物学方法用于确定 PRMT6 调节 DN 中铁死亡的潜在机制。我们的结果表明，PRMT6 下调通过调节 DN 中的铁死亡参与肾功能障碍和肾细胞死亡。此外，PRMT6 还原通过上调酰基辅酶 A 合成酶长链家族成员 1 （ACSL1） 表达诱导脂质过氧化，最终导致铁死亡。此外，我们研究了 PRMT6 与信号转导和转录激活因子 1 （STAT1） 相互作用以共同调节 ACSL1 转录的分子机制。此外，用 STAT1 特异性抑制剂氟达拉滨治疗延缓了 DN 进展。此外，我们观察到 PRMT6 和 STAT1 协同调节 ACSL1 转录以介导高血糖细胞中的铁死亡。我们的研究表明，PRMT6 和 STAT1 协同调节 ACSL1 转录以诱导磷脂-多不饱和脂肪酸 （PL-PUFAs） 的产生，从而参与 DN 中的铁死亡。这些发现表明 PRMT6/STAT1/ACSL1 轴是预防和治疗 DN 的新治疗靶点。