From Stable Radicals to Radical‑Trapping Antioxidants: Blatter Radicals Potently Inhibit Autoxidation and Suppress Ferroptosis

ABSTRACT Ferroptosis is a clinically important form of regulated cell death implicated in numerous degenerative pathologies, making the discovery of novel ferroptosis inhibitors of great translational interest. Radical‑trapping antioxidants (RTAs) effectively prevent lipid peroxidation (LPO) and constitute the largest and most important class of ferroptosis inhibitors. However, current approaches for compound discovery and mechanistic studies rely almost exclusively on phenolic or aromatic amine scaffolds, which are typically identified via labor‑intensive high‑throughput screening or adapted from classical antioxidants. Here, we demonstrate that Blatter radicals potently inhibit autoxidation and suppress ferroptosis. Beyond their intrinsic potent radical‑trapping capability, these compounds exhibit super‑stoichiometric activity in inhibiting (phospho)lipid peroxidation through an unusual catalytic cross‑dismutation of lipid peroxyl radicals (LOO•) and hydroperoxyl radicals (HOO•). Importantly, this potent chemical reactivity translates effectively into biological systems: Blatter radicals confer broad anti‑ferroptotic cytoprotection at low nanomolar concentrations, effectively protect against oxygen‑glucose deprivation/reperfusion (OGD/R) injury, and exert strong anti‑inflammatory effects in lipopolysaccharide (LPS)‑stimulated BV2 microglial cells. Collectively, our results highlight the unprecedented versatility of Blatter radicals—extending from stable radicals to RTAs—and validate a rational design strategy for potent ferroptosis inhibitors.