铁死亡是一种细胞死亡方式，在治疗包括透明细胞肾细胞癌（ccRCC）在内的许多癌症方面具有巨大的应用潜力。在本研究中，我们发现Kruppel样因子11（KLF11）在抑制ccRCC进展中具有关键作用。通过分析来自基因表达纲目（GEO）数据库的mRNA表达数据，我们发现KLF11是ccRCC组织中明显下调的基因。随后的功能实验证实，KLF11在ccRCC细胞和异种移植瘤中起到抗增殖作用。此外，基因集富集分析表明，铁死亡参与了ccRCC的发展，相关性分析显示KLF11与铁死亡驱动因子呈正相关。我们还发现，KLF11通过下调铁蛋白、系统xc（-）半胱氨酸/谷胱甘肽抗porter（xCT）和谷胱甘肽过氧化物酶4（GPX4）的蛋白表达，促进ccRCC的铁死亡，作为铁死亡的抑制因子增加脂质活性氧的胞内水平。作为转录调控因子，KLF11显着增加了胞核受体共激活因子4（NCOA4）的启动子活性，NCOA4在ccRCC中明显下调，其低表达与不良生存相关。KLF11过表达引起的ccRCC细胞特征在NCOA4沉默后被逆转。总之，本研究表明KLF11通过增加NCOA4的转录抑制ccRCC的进展。因此，KLF11 / NCOA4轴可能成为人类ccRCC的一种新的治疗靶点。©2023。作者在日本人类细胞学会的独家许可下发表。

Ferroptosis is a form of cell death and has great potential application in the treatment of many cancers, including clear cell renal cell carcinoma (ccRCC). Herein, we identified the essential roles of Krüppel-like factor 11 (KLF11) in suppressing the progression of ccRCC. By analyzing mRNA expression data from the Gene Expression Omnibus (GEO) database, we found that KLF11 was a significantly downregulated gene in ccRCC tissues. The results of subsequent functional assays verified that KLF11 played an antiproliferative role in ccRCC cells and xenograft tumors. Furthermore, gene set enrichment analysis indicated that ferroptosis was involved in ccRCC development, and correlation analysis revealed that KLF11 was positively related to ferroptosis drivers. We also found that KLF11 promoted ferroptosis in ccRCC by downregulating the protein expression of ferritin, system xc (-) cystine/glutamate antiporter (xCT), and glutathione peroxidase 4 (GPX4), acting as the inhibitory factors of ferroptosis and increasing the intracellular levels of lipid reactive oxygen species (ROS). As a transcriptional regulator, KLF11 significantly increased the promoter activity of nuclear receptor coactivator 4 (NCOA4), a gene significantly downregulated in ccRCC and whose low expression is associated with poor survival. The characteristics of ccRCC cells caused by KLF11 overexpression were reversed after NCOA4 silencing. In summary, the present study suggests that KLF11 suppresses the progression of ccRCC by increasing NCOA4 transcription. Therefore, the KLF11/NCOA4 axis may serve as a novel therapeutic target for human ccRCC.© 2023. The Author(s) under exclusive licence to Japan Human Cell Society.