Oncogenic HNF4α inhibits ferroptotic cell death through activating SLC7A11 by recruiting p300/CBP in breast cancer

As an iron-dependent novel form of cell death caused by the accumulation of lipid peroxides, ferroptosis has been gradually recognized as a new cancer therapeutic target in recent years. Although the precise mechanisms underlying iron-induced cell death remain incompletely elucidated, this study identifies its distinctive role. A decrease in hepatocyte nuclear factor 4-alpha (HNF4α) activity could increase ferroptosis in breast cancer (BC) cells both in vitro and in vivo. Mechanistically, it was found that HNF4α binds directly to the promoter of SLC7A11, where it recruits the histone acetyltransferase p300/CBP to promote transcription of SLC7A11. Our study shows that HNF4α is crucial for ferroptosis in breast cancer, which may open up the possibility of developing a new therapeutic approach for advanced cancers resistant to chemotherapy.