Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation

• DOI: 10.1016/j.redox.2021.101942
• Publication Date: 2021-03-14T06:49:34Z
• Authors: Jialei Sun; Chenhao Zhou; Yue Zhao; Xiaofei Zhang; Wanyong Chen; Qiang Zhou; Bo Hu; Dongmei Gao; Lisa Raatz; Zhefang Wang; Peter J. Nelson; Yuchao Jiang; Ning Ren; Christiane J. Bruns; Haijun Zhou
• Keywords: Medicine (General); 0303 health sciences; Carcinoma, Hepatocellular; QH301-705.5; NF-E2-Related Factor 2; Liver Neoplasms; ROS; Sorafenib; 3. Good health; ErbB Receptors; 03 medical and health sciences; R5-920; Cell Line, Tumor; QSOX1; Ferroptosis; Humans; Oxidoreductases Acting on Sulfur Group Donors; HCC; Antioxidant; Biology (General); Oxidoreductases; Research Paper

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), but its clinical effects are still limited. In this study we identify Quiescin sulfhydryl oxidase 1 (QSOX1) acting as cellular pro-oxidant, specifically in the context of sorafenib treatment HCC. QSOX1 disrupts redox homoeostasis and sensitizes HCC cells to oxidative stress by inhibiting activation master antioxidant transcription factor NRF2. A negative correlation between NRF2 expression was validated tumor tissues from 151 patients. Mechanistically, restrains EGF-induced EGFR promoting ubiquitination-mediated degradation accelerating intracellular endosomal trafficking, leading suppression activity. Additionally, potentiates sorafenib-induced ferroptosis suppressing vitro vivo. conclusion, data presented novel candidate target sorafenib-based combination therapeutic strategies or other EGFR-dependent types.