The IDH1-R132H mutation is implicated in the development of various tumors. Whether cisplatin, a common chemotherapeutic agent, induces more significant renal toxicity in individuals with the IDH1-R132H mutation remains unclear. In this study, we observed that the IDH1-R132H mutation exacerbates mitochondrial lipid peroxidation and dysfunction in renal tubules, rendering the kidneys more susceptible to cisplatin-induced ferroptosis. The IDH1-R132H mutation increases methylation of the Ndufa1 promoter, thereby suppressing NDUFA1 transcription and translation. This suppression disrupts NDUFA1’s interaction with FSP1, reducing its resistance to cisplatin-induced tubular epithelial cell death. As a consequence, ROS accumulates, lipid peroxidation occurs, and ferroptosis is triggered, thereby promoting acute kidney injury. In summary, this study elucidates a novel mechanism underlying cisplatin-induced nephrotoxicity and provides valuable insights for the development of personalized treatment strategies for tumor patients carrying the IDH1-R132H mutation.

IDH1-R132H 突变与多种肿瘤的发生有关。顺铂（一种常见的化疗药物）是否会在 IDH1-R132H 突变个体中引起更显着的肾毒性仍不清楚。在这项研究中，我们观察到 IDH1-R132H 突变加剧了线粒体脂质过氧化和肾小管功能障碍，使肾脏更容易受到顺铂诱导的铁死亡的影响。 IDH1-R132H 突变增加了Ndufa1启动子的甲基化，从而抑制 NDUFA1 转录和翻译。这种抑制破坏了 NDUFA1 与 FSP1 的相互作用，降低了其对顺铂诱导的肾小管上皮细胞死亡的抵抗力。结果，ROS积累，发生脂质过氧化，引发铁死亡，从而促进急性肾损伤。总之，本研究阐明了顺铂诱导肾毒性的新机制，并为携带 IDH1-R132H 突变的肿瘤患者制定个性化治疗策略提供了宝贵的见解。