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Redox Biology

Redox Biology

IF: 10.7
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ATF7IP inhibits Sorafenib-induced ferroptosis in hepatocellular carcinoma cells by inhibiting CYB5R2 transcription and stabilizing PARK7 protein

Published:24 July 2025 DOI: 10.1016/j.redox.2025.103786
Yijie Su , Sirui Huang , Yang Duan , Liang Zhang , Shengyun Feng , Yingge Lv , Bei Lan , Chenghao Xuan

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.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 247 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 247 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 247 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 247 suppliers $10.00-$2822.00
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