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  3. SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation

SMURF2 predisposes cancer cell toward ferroptosis in GPX4-independent manners by promoting GSTP1 degradation

  • Mol Cell. 2023 Nov 16:S1097-2765(23)00913-9. doi: 10.1016/j.molcel.2023.10.042.
Wenxin Zhang 1,  Junren Dai 2,  Guixue Hou 3,  Hao Liu 2,  Shanliang Zheng 2,  Xingwen Wang 2,  Qingyu Lin 2,  Yi Zhang 2,  Minqiao Lu 2,  Yafan Gong 2,  Zhiyuan Xiang 2,  Yan Yu 4,  Ying Hu 5
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou 450000, China.
  • 2 School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
  • 3 BGI-SHENZHEN, Shenzhen 518083, China.
  • 4 Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • 5 School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China; Key Laboratory of Science and Engineering for the Multi-modal Prevention and Control of Major Chronic Diseases, Ministry of Industry and Information Technology, HIT Zhengzhou Research Institute, Zhengzhou 450000, China. Electronic address: huying@hit.edu.cn.
PMID: 38016474 DOI: 10.1016/j.molcel.2023.10.042
Abstract

Ferroptosis is a non-apoptotic form of regulated cell death. Glutathione (GSH) peroxidase 4 (GPX4) and GSH-independent Ferroptosis suppressor protein 1 (FSP1) have been identified as major defenses. Here, we uncover a protective mechanism mediated by GSH S-transferase P1 (GSTP1) by monitoring proteinomic dynamics during Ferroptosis. Dramatic downregulation of GSTP1 is caused by SMURF2-mediated GSTP1 ubiquitination and degradation at early stages of Ferroptosis. Intriguingly, GSTP1 acts in GPX4- and FSP1-independent manners by catalyzing GSH conjugation of 4-hydroxynonenal and detoxifying lipid hydroperoxides via selenium-independent GSH peroxidase activity. Genetic modulation of the SMURF2/GSTP1 axis or the pharmacological inhibition of GSTP1's catalytic activity sensitized tumor responses to Food and Drug Administration (FDA)-approved ferroptosis-inducing drugs both in vitro and in vivo. GSTP1 expression also confers resistance to Immune Checkpoint inhibitors by blunting Ferroptosis. Collectively, these findings demonstrate a GPX4/FSP1-independent cellular defense mechanism against Ferroptosis and suggest that targeting SMURF2/GSTP1 to sensitize Cancer cells to Ferroptosis has potential as an Anticancer therapy.

Keywords

GSH conjugation; GSTP1; SMURF2; ferroptosis; selenium-independent GSH peroxidase.

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