Endogenous chemicals guard health through inhibiting ferroptotic cell death

Ferroptosis is a new form of regulated cell death caused by iron-dependent accumulation of lethal polyunsaturated phospholipids peroxidation. It has received considerable attention owing to its putative involvement in a wide range of pathophysiological processes such as organ injury, cardiac ischemia/reperfusion, degenerative disease and its prevalence in plants, invertebrates, yeasts, bacteria, and archaea. To counter ferroptosis, living organisms have evolved a myriad of intrinsic efficient defense systems, such as cyst(e)ine-glutathione-glutathione peroxidase 4 system (cyst(e)ine-GPX4 system), guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin (BH₄) system (GCH1/BH₄ system), ferroptosis suppressor protein 1/coenzyme Q₁₀ system (FSP1/CoQ₁₀ system), and so forth. Among these, GPX4 serves as the only enzymatic protection system through the reduction of lipid hydroperoxides, while other defense systems ultimately rely on small compounds to scavenge lipid radicals and prevent ferroptotic cell death. In this article, we systematically summarize the chemical biology of lipid radical trapping process by endogenous chemicals, such as coenzyme Q₁₀ (CoQ₁₀), BH₄, hydropersulfides, vitamin K, vitamin E, 7-dehydrocholesterol, with the aim of guiding the discovery of novel ferroptosis inhibitors.