Polycyclic quinone compounds containing a six-membered silacycle suppress ferroptosis in vitro

Ferroptosis is a regulated form of cell death implicated in a wide range of pathological conditions. Iron-dependent lipid peroxidation driven by reactive oxygen species is a central feature. Because ferroptosis contributes to oxidative stress-induced tissue injury, including ischemia-reperfusion damage and neurodegenerative disorders, the suppression of this process has attracted considerable interest. Through a phenotypic screen of a unique chemical compound library from the University of Osaka, we identified a series of polycyclic quinone compounds containing a six-membered silacycle that exhibited protective effects against ferroptosis in vitro. These compounds selectively suppressed ferroptosis induced by various distinct ferroptosis inducers, while showing no protective effects against apoptosis. The ferroptosis-suppressive effects of these compounds were associated with reduced lipid peroxidation and decreased accumulation of ferrous iron in the mitochondria. Direct comparison with a carbon-substituted analog revealed that silicon substitution within the polycyclic quinone scaffold markedly enhanced the ferroptosis-suppressive activity. These results indicate that silicon-containing polycyclic quinone compounds represent a selective class of ferroptosis inhibitors and that silicon substitution confers a functional advantage for ferroptosis suppression.