Identification of a novel tetrahydroxynaphthalene derivative by chemical screening with ferroptosis inhibitory activity and promising therapeutic potential

Hydroxyl radicals produced by the iron-mediated Fenton reaction are highly reactive, increase lipid peroxide levels, and damage cell membranes, resulting in ferroptosis, an iron-dependent form of cell death. In recent years, the role of ferroptosis in various pathological conditions has garnered interest. Because it is responsible for oxidative stress-induced organ damage, especially cell death associated with ischemia-reperfusion injury and neurological disorders, the inhibition of ferroptosis may ameliorate organ damage. Through a screen of a unique chemical compound library from Osaka University, we identified several structurally distinct compounds that were highly protective against ferroptosis <i>in vitro</i>. Notably, compound #562, which is a tetrahydroxynaphthalene derivative, exhibited a remarkable ability to fully rescue cells from ferroptosis at low concentrations (0.1 µM). A computational analysis revealed its structural uniqueness and high drug-likeness score, indicating its clinical potential. Along with its enhanced efficacy, this suggests that compound #562 may provide alternative modes of action or improved therapeutic potential for ferroptosis-related diseases.