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

  • Biochim Biophys Acta Mol Basis Dis. 2025 Aug;1871(6):167884. doi: 10.1016/j.bbadis.2025.167884.
Zhuang Wang  1 ,  Sen Xu  1 ,  Jinxia Hu  1 ,  Hongfang Sun  1 ,  Yuan Yu  1 ,  Shuling Song  2 ,  Shuyang Xie  3 ,  Guangbin Sun  4
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, PR China.
  • 2. Department of Immunology, Binzhou Medical University, YanTai, ShanDong 264003, PR China.
  • 3. Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, PR China. Electronic address: [email protected].
  • 4. Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, PR China. Electronic address: [email protected].
PMID: 40320185 DOI: 10.1016/j.bbadis.2025.167884
Abstract

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.

Keywords
Breast cancer; Ferroptosis; HNF4α protein; SLC7A11.
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