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.
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BibTeX
@article{tian2026klf4slc25a4,
title = {{The KLF4–SLC25A4 mitochondrial axis regulates ferroptotic vulnerability and sunitinib sensitivity in clear cell renal cell carcinoma}},
author = {Shuo Tian and HaiRui Chen and WenLei Zhao and DongLai Shen and Chuang Wang and XuPeng Zhao and HaiTao Liu and Xin Ma and Xu Zhang and HaiXing Mai},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-70052-0},
url = {https://www.nature.com/articles/s41598-026-70052-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The KLF4–SLC25A4 mitochondrial axis regulates ferroptotic vulnerability and sunitinib sensitivity in clear cell renal cell carcinoma
AU - Shuo Tian
AU - HaiRui Chen
AU - WenLei Zhao
AU - DongLai Shen
AU - Chuang Wang
AU - XuPeng Zhao
AU - HaiTao Liu
AU - Xin Ma
AU - Xu Zhang
AU - HaiXing Mai
PY - 2026
DA - 2026/10/14
JO - Scientific Reports
DO - 10.1038/s41598-026-70052-0
UR - https://www.nature.com/articles/s41598-026-70052-0
AB - 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.
SN - 2045-2322
ER -