Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma
Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma
复制标题
索拉非尼通过抑制肝细胞癌中的 HBXIP/SCD 轴引发铁死亡
DOI：
10.1038/s41401-022-00981-9
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发表时间：
2022-09-15
影响因子：
8.2
通讯作者：
Ye, Li-hong
中科院分区：
文献类型：
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作者：
Zhang, Lu;Li, Xian-meng;Ye, Li-hong
索拉非尼抑制多种激酶，是肝细胞癌（HCC）的有效一线治疗药物。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形式，可由索拉非尼治疗诱导。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、耐药和代谢重编程。然而，HBXIP在索拉非尼诱导的铁致细胞死亡中的作用尚不清楚。在这项研究中，我们证明HBXIP可以阻止索拉非尼诱导的HCC细胞铁下垂。索拉非尼降低HBXIP表达，HBXIP过表达阻断索拉非尼诱导的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凋亡和细胞死亡。Ferrostatin-1，一种铁ptosis抑制剂，在HCC细胞中逆转了HBXIP沉默引起的sorafenib增强的抗癌作用。分子机制方面，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）表达，导致游离脂肪酸积累，抑制铁下沉。在功能上，HBXIP/SCD轴的激活降低了索拉非尼的抗癌活性，抑制了体内和体外的铁致细胞死亡。HBXIP/SCD轴介导的铁凋亡可以作为索拉非尼的一种新的下游效应。我们的结果为HCC治疗的临床决策提供了新的证据。
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.