2. Academic Validation
  3. Phosphorylated FOXQ1, a novel substrate of JNK1, inhibits sorafenib-induced ferroptosis by activating ETHE1 in hepatocellular carcinoma

Phosphorylated FOXQ1, a novel substrate of JNK1, inhibits sorafenib-induced ferroptosis by activating ETHE1 in hepatocellular carcinoma

  • Cell Death Dis. 2024 Jun 5;15(6):395. doi: 10.1038/s41419-024-06789-1.
Yiwei Liu # 1,  Ke Shao # 1 2,  Wendong Yang # 3,  Qi Shen 3,  Mengru Lu 3,  Zhiying Shao 3,  Sufang Chu 3,  Yuming Wang 1,  Xuehao Wang 4,  Xiaofeng Chen 5,  Jin Bai 6 7,  Xiaofeng Wu 8
Affiliations

Affiliations

  • 1 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.
  • 2 Department of General Surgery, The People's Hospital of Rugao, Affiliated Rugao Hospital of Nantong University, Nantong, Jiangsu Province, China.
  • 3 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
  • 4 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. wangxh@njmu.edu.cn.
  • 5 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China. chenxiaofengnjmu@163.com.
  • 6 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. bj@xzhmu.edu.cn.
  • 7 Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China. bj@xzhmu.edu.cn.
  • 8 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. wuxf@njmu.edu.cn.
  • # Contributed equally.
PMID: 38839744 DOI: 10.1038/s41419-024-06789-1
Abstract

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.

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