2. Academic Validation
  3. CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes

CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes

  • Nat Chem Biol. 2024 Jan 11. doi: 10.1038/s41589-023-01512-1.
Zili Zhang # 1,  Hong Zhou # 1,  Wenjia Gu # 2 3,  Yuehan Wei 4,  Shan Mou 4,  Youjun Wang 5 6,  Jing Zhang 7,  Qing Zhong 8
Affiliations

Affiliations

  • 1 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, China.
  • 3 Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China.
  • 4 Department of Nephrology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, China. [email protected].
  • 6 Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China. [email protected].
  • 7 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8 Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 38212578 DOI: 10.1038/s41589-023-01512-1
Abstract

Ferroptosis is iron-dependent oxidative cell death. Labile iron and polyunsaturated fatty acid (PUFA)-containing lipids are two critical factors for Ferroptosis execution. Many processes regulating iron homeostasis and lipid synthesis are critically involved in Ferroptosis. However, it remains unclear whether biological processes other than iron homeostasis and lipid synthesis are associated with Ferroptosis. Using kinase inhibitor library screening, we discovered a small molecule named CGI1746 that potently blocks Ferroptosis. Further studies demonstrate that CGI1746 acts through sigma-1 receptor (σ1R), a chaperone primarily located at mitochondria-associated membranes (MAMs), to inhibit Ferroptosis. Suppression of σ1R protects mice from cisplatin-induced acute kidney injury hallmarked by Ferroptosis. Mechanistically, CGI1746 treatment or genetic disruption of MAMs leads to defective Ca2+ transfer, mitochondrial Reactive Oxygen Species (ROS) production and PUFA-containing triacylglycerol accumulation. Therefore, we propose a critical role for MAMs in Ferroptosis execution.

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