Novel Carboline-Based Ferroptosis Inhibitor Ameliorates Acute Liver Injury by Remodeling Phosphatidylcholine

  • J Med Chem. 2026 May 14;69(9):11503-11523. doi: 10.1021/acs.jmedchem.6c00720.
Lijie Lv  1 ,  Xuan Li  1 ,  Biwen Wan  1 ,  Yijie Xiao  1 ,  Fang Lin  1 ,  Mengjie Huang  1 ,  Jingsong Zhang  1 ,  Hao Chen  2 ,  Yahui Zhao  1 ,  Yi He  1 ,  Hai-Xin Yuan  1 ,  Shenyou Nie  1
Affiliations
  • 1. Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Department of Urology and Department of Cancer Center of the Second Affiliated Hospital, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
  • 2. Molecular Imaging Center, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 42059576 DOI: 10.1021/acs.jmedchem.6c00720
Abstract

Ferroptosis is an iron-dependent form of cell death caused by phospholipid peroxidation and represents a therapeutic target for acute organ injury. Regulating cellular lipid composition to control peroxidation-prone Phospholipids is crucial for modulating Ferroptosis. We synthesized 53 carboline derivatives featuring a benzofuro[2,3-b]pyridine scaffold via a rhodium-catalyzed cascade reaction. Phenotypic screening identified compound 4g as a potent Ferroptosis inhibitor, with an EC50 value of 93 nM in H9c2 cells. Mechanistically, 4g neither traps radicals nor chelates iron, nor does it regulate ferroptosis-related gene expression; instead, it mediates CEPT1-dependent phosphatidylcholine remodeling to enrich PC-MUFA and suppress lipid peroxidation. In vivo, 4g effectively protects against hepatic ischemia-reperfusion injury, as well as ConA- and APAP-induced acute liver injury, demonstrating its potential as a promising therapeutic agent for ferroptosis-related tissue damage.

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