2. Academic Validation
  3. ATF7IP inhibits Sorafenib-induced ferroptosis in hepatocellular carcinoma cells by inhibiting CYB5R2 transcription and stabilizing PARK7 protein

ATF7IP inhibits Sorafenib-induced ferroptosis in hepatocellular carcinoma cells by inhibiting CYB5R2 transcription and stabilizing PARK7 protein

  • Redox Biol. 2025 Sep:85:103786. doi: 10.1016/j.redox.2025.103786.
Yijie Su 1,  Sirui Huang 1,  Yang Duan 2,  Liang Zhang 3,  Shengyun Feng 1,  Yingge Lv 1,  Bei Lan 1,  Chenghao Xuan 4
Affiliations

Affiliations

  • 1 Key Laboratory of Breast Cancer Prevention and Therapy (Tianjin Medical University), Ministry of Education; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; Key Laboratory of Immune Microenvironment and Disease (Tianjin Medical University), Ministry of Education; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
  • 2 Clinical Laboratory, Weifang People's Hospital, Shandong Second Medical University, Weifang, 261000, Shandong, China.
  • 3 Research Center of Translational Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250013, China.
  • 4 Key Laboratory of Breast Cancer Prevention and Therapy (Tianjin Medical University), Ministry of Education; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; Key Laboratory of Immune Microenvironment and Disease (Tianjin Medical University), Ministry of Education; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. Electronic address: chenghaoxuan@tmu.edu.cn.
PMID: 40716153 DOI: 10.1016/j.redox.2025.103786
Abstract

Ferroptosis, an iron-dependent form of programmed cell death, arises from the accumulation of lipid peroxides at toxic levels. Sorafenib, a first-line treatment for advanced hepatocellular carcinoma, shows limited clinical efficacy due to drug resistance. However, the mechanisms underlying Sorafenib resistance, especially related to Ferroptosis, remain poorly understood. In this study, we identify activating transcription factor 7-interacting protein (ATF7IP) as a key inhibitor of Ferroptosis. ATF7IP depletion promotes Sorafenib-induced Ferroptosis, resulting in decreased cell viability, reduced cellular glutathione (GSH) levels, increased lipid peroxidation, and altered mitochondrial crista structure. Notably, ATF7IP knockdown shows cooperative effects with Sorafenib in inhibiting hepatocellular carcinoma growth in mice. Mechanistically, ATF7IP interacts with SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to epigenetically silence the transcription of cytochrome b5 reductase 2 (CYB5R2), thereby reducing cellular Fe2+ levels. Meanwhile, ATF7IP stabilizes the antioxidant sensor Parkinsonism-associated deglycase (PARK7) protein which preserves the transsulfuration pathway to produce GSH, also leading to the inhibition of Sorafenib-induced Ferroptosis. In conclusion, our findings identify ATF7IP as a critical Ferroptosis inhibitor and represent ATF7IP as a novel therapeutic target for Sorafenib-based combination therapies of hepatocellular carcinoma.

Keywords

ATF7IP; Ferroptosis; Hepatocellular carcinoma; Sorafenib.

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