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.

索拉非尼可抑制多种激酶，是治疗肝细胞癌 (HCC) 的有效一线疗法。铁死亡是一种由脂质过氧化调节的铁依赖性程序性细胞死亡，可以通过索拉非尼治疗诱导。癌蛋白乙型肝炎 X 相互作用蛋白 (HBXIP) 参与多种生物促肿瘤过程，包括生长、转移、耐药性和代谢重编程。然而，HBXIP 在索拉非尼诱导的铁死亡细胞死亡中的作用仍不清楚。在这项研究中，我们证明 HBXIP 可预防索拉非尼诱导的 HCC 细胞铁死亡。索拉非尼降低 HBXIP 的表达，而 HBXIP 的过度表达可阻止索拉非尼诱导的 HCC 细胞死亡。有趣的是，抑制 HBXIP 会增加丙二醛 (MDA) 的产生和谷胱甘肽 (GSH) 的消耗，从而促进索拉非尼介导的铁死亡和细胞死亡。 Ferrostatin-1 是一种铁死亡抑制剂，可逆转索拉非尼在 HCC 细胞中因 HBXIP 沉默而增强的抗癌作用。就分子机制而言，HBXIP通过共激活转录因子ZNF263转录诱导硬脂酰辅酶A去饱和酶(SCD)的表达，导致游离脂肪酸的积累并抑制铁死亡。从功能上讲，HBXIP/SCD 轴的激活降低了索拉非尼的抗癌活性，并在体内和体外抑制了铁死亡细胞死亡。 HBXIP/SCD 轴介导的铁死亡可以作为索拉非尼的新型下游效应器。我们的结果为 HCC 治疗的临床决策提供了新的证据。