The KLF4–SLC25A4 mitochondrial axis regulates ferroptotic vulnerability and sunitinib sensitivity in clear cell renal cell carcinoma

Abstract Sunitinib resistance remains a major therapeutic challenge in clear cell renal cell carcinoma (ccRCC). Through integrated transcriptomic profiling and mitochondrial gene screening, we identified SLC25A4 as a ferroptosis-associated tumor suppressor. SLC25A4 expression was significantly downregulated in ccRCC tissues and correlated with poor prognosis, advanced stage, and increased invasiveness. Functional assays revealed that SLC25A4 inhibits tumor proliferation and invasion by promoting ferroptosis, elevating reactive oxygen species (ROS), impairing mitochondrial membrane potential, and suppressing antioxidant defense. Mechanistically, we identified KLF4 as an upstream transcription factor of SLC25A4, regulating its expression in a promoter motif-dependent manner. KLF4 expression was reduced in tumors and positively correlated with SLC25A4 levels and patient survival. KLF4 overexpression reactivated SLC25A4 transcription, restored ferroptotic signaling, and inhibited tumor growth. Importantly, the KLF4–SLC25A4 axis sensitized ccRCC cells to sunitinib in vitro and in vivo. Knockdown of either KLF4 or SLC25A4 conferred drug resistance, whereas KLF4 re-expression re-sensitized resistant cells by enhancing oxidative stress and mitochondrial dysfunction. Clinical tissue analysis confirmed reduced SLC25A4 expression in sunitinib-resistant tumors. Together, our findings uncover a previously unrecognized KLF4–SLC25A4 regulatory axis that contributes to ferroptosis and therapeutic response, offering a potential strategy to improve sunitinib sensitivity in ccRCC.