Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma

Lu Zhang1, Xian-meng Li1, Xu-he Shi1, Kai Ye1, Xue-li Fu1, Xue Wang1, Shi-man Guo1, Jia-qi Ma1, Fei-fei Xu1, Hui-min Sun1, Qian-qian Li1, Wei-ying Zhang1, Li-hong Ye1
1 State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
Correspondence to: Qian-qian Li:,
DOI: 10.1038/s41401-022-00981-9
Received: 6 May 2022
Accepted: 11 August 2022
Advance online: 15 September 2022


Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy.
Keywords: HBXIP; SCD; ferroptosis; sorafenib; ZNF263; hepatocellular carcinoma

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