Chen Jinjing, Trindl Carlee A, Ye Haofeng, Huang Dichun, Ooi Aikseng, Garcia Joe G N, Chapman Eli, Zhang Donna D
Department of Molecular Medicine, Center for Inflammation Science and Systems Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida, USA.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Mol Carcinog. 2025 Jul;64(7):1264-1274. doi: 10.1002/mc.23925. Epub 2025 May 6.
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related mortality globally. Current systemic therapies for HCC are limited and often exhibit unsatisfactory efficacy, underscoring the need for novel therapeutic approaches. Nuclear factor erythroid 2-related factor-2 (NRF2), a master transcription factor regulating cellular redox and metabolic homeostasis, is frequently overexpressed in HCC due to mutations in NFE2L2/NRF2 or its negative regulator Kelch-like ECH-associated protein 1 (KEAP1), contributing to tumor progression. In this study, we identify CYP4F11, a member of the Cytochrome P450 family, as a direct target gene of NRF2. CYP4F11, primarily expressed in the liver, is crucial in fatty acid oxidation and eicosanoid metabolism. We demonstrate that CYP4F11 expression is driven by NRF2 and is significantly elevated in HCC patients harboring NFE2L2 gain of function or KEAP1 loss of function mutations. Functionally, CYP4F11 promotes HCC cell growth, and reduced expression of CYP4F11 not only suppresses HCC cell proliferation but also enhances sorafenib-induced HCC cell death. Further, NRF2 inhibition sensitizes HCC to sorafenib through downregulation of CYP4F11. These findings position CYP4F11 as a novel contributor to HCC progression and highlight the potential of targeting the NRF2-CYP4F11 axis for HCC treatment.
肝细胞癌（HCC）是原发性肝癌最常见的形式，是全球癌症相关死亡的第三大主要原因。目前用于HCC的全身治疗方法有限，且疗效往往不尽人意，这凸显了对新型治疗方法的需求。核因子红细胞2相关因子2（NRF2）是一种调节细胞氧化还原和代谢稳态的主要转录因子，由于NFE2L2/NRF2或其负调节因子 Kelch样ECH相关蛋白1（KEAP1）发生突变，在HCC中经常过度表达，促进肿瘤进展。在本研究中，我们确定细胞色素P450家族成员CYP4F11是NRF2的直接靶基因。CYP4F11主要在肝脏中表达，在脂肪酸氧化和类花生酸代谢中起关键作用。我们证明CYP4F11的表达由NRF2驱动，并且在携带NFE2L2功能获得或KEAP1功能丧失突变的HCC患者中显著升高。在功能上，CYP4F11促进HCC细胞生长，CYP4F11表达降低不仅抑制HCC细胞增殖，还增强索拉非尼诱导的HCC细胞死亡。此外，NRF2抑制通过下调CYP4F11使HCC对索拉非尼敏感。这些发现将CYP4F11定位为HCC进展的新促成因素，并突出了靶向NRF2-CYP4F11轴治疗HCC的潜力。
