Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
Department of General Surgery, The People's Hospital of Rugao, Affiliated Rugao Hospital of Nantong University, Nantong, Jiangsu Province, China.
Cell Death Dis. 2024 Jun 5;15(6):395. doi: 10.1038/s41419-024-06789-1.
Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant cancer with poor overall survival. The application of sorafenib is a major breakthrough in the treatment of HCC. In our study, FOXQ1 was significantly overexpressed in sorafenib-resistant HCC cells and suppressed sorafenib-induced ferroptosis. We found that phosphorylation of FOXQ1 at serine 248 is critical for the suppression of sorafenib-induced ferroptosis. Furthermore, as the upstream phosphorylation kinase of FOXQ1, JNK1, which is activated by sorafenib, can directly phosphorylate the serine 248 site of FOXQ1. Then, the phosphorylated FOXQ1 got a high affinity for the promoter of ETHE1 and activates its transcription. Further flow cytometry results showed that ETHE1 reduced intracellular lipid peroxidation and iron levels. Collectively, our study implicated the JNK1-FOXQ1-ETHE1 axis in HCC ferroptosis induced by sorafenib, providing mechanistic insight into sensitivity to sorafenib therapy of HCC.
肝细胞癌（HCC）是一种高度异质性和恶性肿瘤，整体生存率较差。索拉非尼的应用是 HCC 治疗的重大突破。在我们的研究中，FOXQ1 在索拉非尼耐药 HCC 细胞中显著过表达，并抑制索拉非尼诱导的铁死亡。我们发现 FOXQ1 丝氨酸 248 位的磷酸化对于抑制索拉非尼诱导的铁死亡至关重要。此外，作为 FOXQ1 的上游磷酸化激酶，JNK1 被索拉非尼激活后，可直接磷酸化 FOXQ1 的丝氨酸 248 位。然后，磷酸化的 FOXQ1 与 ETHE1 启动子具有高亲和力，并激活其转录。进一步的流式细胞术结果表明，ETHE1 降低了细胞内脂质过氧化和铁水平。综上所述，我们的研究表明 JNK1-FOXQ1-ETHE1 轴在索拉非尼诱导的 HCC 铁死亡中起作用，为 HCC 对索拉非尼治疗的敏感性提供了机制见解。
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