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

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.