Cytochrome P450 F3 promotes colorectal cancer via inhibiting NRF2-mediated ferroptosis

• Published in: Translational oncology 2024-10, Vol.48, p.102077, Article 102077
• Main Authors: Xu, Ziyang, Xu, Cheng, Lu, Jie, He, Chenfeng, Wang, Xinyue, Zhu, Dongfei, Wang, Aizhong, Zhang, Zhengyun, Jiang, Can
• Format: Article
• Language: English
• Subjects: Colorectal cancer; CYP4F3; Cytochrome P450; Ferroptosis; NRF2; Original Research
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2024.102077

•Identification of CYP4F3 as a potential biomarker for CRC prognosis based on its upregulation in tumor tissues and association with poor patient survival.•Elucidation of the role of CYP4F3 in promoting CRC cell proliferation and migration, accompanied by a reduction in cellular oxidative stress.•Demonstration of the inhibitory effect of CYP4F3 on NRF2-mediated ferroptosis, highlighting its significance in CRC development and progression.•Validation of our in vitro findings through in vivo experiments using a murine CRC model, further confirming the oncogenic role of CYP4F3 in CRC progression. Cytochrome P450 F3 (CYP4F3) is recognized as a disease-associated immune response initiator that is involved in the synthesis of cholesterol, steroids, and lipids. This study identified the upregulation of CYP4F3 expression in colorectal cancer (CRC) and its association with poor patient prognosis through a comparative analysis between CRC tumor tissues with normal tissues from public databases. The overexpression of CYP4F3 in CT26.wt and SW620, promoted cell proliferation and migration, a reduction of cellular oxidative stress, an up-regulation of the oxidative stress-related pathway NRF2, and an inhibition of cellular ferroptosis. Additionally, inhibition of NRF2 activity stimulated cellular ferroptosis when CYP4F3 was overexpressed. Ferroptosis, characterized by iron-dependent lipid peroxidation, is a non-apoptotic way of cell death with a critical role in cancer development. When given a ferroptosis agonist to CYP4F3-overexpression CRC cells, NRF2 was activated, and cell proliferation and migration were reduced. Furthermore, the mice subcutaneously injected with CYP4F3-overexpression CT26.wt cells formed significantly larger tumors compared to the CYP4F3-vector CT26.wt cell group. This study systematically identified an important role of CYP4F3 in CRC development as a regulator of CRC cells to escape ferroptosis via NRF2, highlighting the significance of CYP4F3 as a potential therapeutic target for CRC.