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

Authors：Zhang, Wenxin; Dai, Junren; Hou, Guixue; Liu, Hao; Zheng, Shanliang; Wang, Xingwen; Lin, Qingyu; Zhang, Yi; Lu, Minqiao; Gong, Yafan; Xiang, Zhiyuan; Yu, Yan; Hu, Ying^*

Source：Molecular Cell, 2023, 83(23).

DOI：10.1016/j.molcel.2023.10.042

• GLUTATHIONE S-TRANSFERASES
• LIPID-PEROXIDATION
• PROTEIN STABILITY
• INDUCED APOPTOSIS
• REDOX REGULATION
• DEATH
• METABOLISM
• COMPLEX
• P1
• MULTICENTER

Ferroptosis is a non-apoptotic form of regulated cell death. Glutathione (GSH) peroxidase 4 (GPX4) and GSHindependent 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.

• Institution
  哈尔滨医科大学; y; 深圳华大基因研究院