The IDH1-R132H mutation aggravates cisplatin-induced acute kidney injury by promoting ferroptosis through disrupting NDUFA1 and FSP1 interaction
Kunmei Lai, Zhimin Chen, Siyi Lin, Keng Ye, Ying Yuan, Guoping Li, Yankun Song, Huabin Ma, Tak W. Mak, Yanfang Xu
Abstract
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.