Ferroptosis is a form of regulated, non-apoptotic cell death characterized by excessive lipid peroxidation that can be triggered by inhibition of the cystine-glutamate antiporter, system Xc - . Sorafenib, an FDA-approved multi-kinase inhibitor drug that is used for treatment of hepatocellular carcinoma (HCC), has been shown to induce ferroptosis. Protein phosphorylation changes upon sorafenib treatment have been previously reported in patient studies and in cell culture. However, early phosphorylation changes during induction of ferroptosis are not reported. This work highlights these changes through a time course from 7 to 60 min of sorafenib treatment in human (SKHep1) HCC cells. A total of 6170 unique phosphosites from 2381 phosphoproteins are quantified, and phosphorylation changes occur after as little as 30 min of sorafenib treatment. By 60 min, notable changes included phosphosites significantly changing on p53 (P04637), CAD protein (P27708), and proteins important for iron homeostasis, such as heavy chain ferritin (FTH1; P02794), heme oxygenase 1 (HMOX1; P09601), and PCBP1 (Q15365). Additional sites on proteins in key regulatory pathways are identified, including sites in ferroptosis-related proteins, indicating the likely involvement of phospho-regulated signaling during ferroptosis induction.

中文翻译：

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索拉非尼治疗的肝细胞癌细胞变化的时间过程表明磷酸调节信号参与铁死亡诱导。

铁死亡是一种受调节的非凋亡细胞死亡形式，其特征是过度的脂质过氧化，可通过抑制胱氨酸-谷氨酸逆向转运蛋白系统 Xc - 来触发。索拉非尼是 FDA 批准的一种多激酶抑制剂药物，用于治疗肝细胞癌 (HCC)，已被证明可诱导铁死亡。先前在患者研究和细胞培养中已报道过索拉非尼治疗后蛋白质磷酸化的变化。然而，尚未报道铁死亡诱导期间的早期磷酸化变化。这项工作强调了索拉非尼在人 (SKHep1) HCC 细胞中治疗 7 至 60 分钟的时间过程中发生的这些变化。总共对 2381 个磷蛋白的 6170 个独特磷酸位点进行了定量，索拉非尼治疗短短 30 分钟后就会发生磷酸化变化。60 分钟时，显着变化包括 p53 (P04637)、CAD 蛋白 (P27708) 和对铁稳态重要的蛋白质（如重链铁蛋白 (FTH1; P02794)、血红素加氧酶 1 (HMOX1; P09601) 和PCBP1 (Q15365)。确定了关键调控途径中蛋白质上的其他位点，包括铁死亡相关蛋白质中的位点，表明在铁死亡诱导过程中可能涉及磷酸调节信号传导。