Ferroptosis‐Inhibitory Effect and Possible Mechanisms of Ellagitannin Geraniin

The search for safe and effective ferroptosis‐inhibitors has become an important topic. Geraniin, an ellagitannin bearing hexahydroxydiphenoyl (HHDP) and dehydrohexahydroxydiphenoyl (DHHDP) groups, was observed to inhibit erastin‐induced ferroptosis in bone marrow‐derived mesenchymal stem cells (bmMSCs). To determine the mechanism, geraniin was further analyzed using UV‐vis spectra and several colorimetric assays, where its IC50 values were always much lower than that of the Trolox positive control. When interacted with several free radicals, geraniin gave no radical adduct formation (RAF) peak in the ultra‐performance liquid chromatography coupled with electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry. In conclusion, geraniin exhibits ferroptosis‐inhibitory potential towards erastin‐treated bmMSCs; such potential may mainly stem from its strong lipid peroxidation (LPO)‐inhibition, Fe2+‐chelating, and antioxidant actions. Geraniin gives neither dimer nor radical adduct, owing to the bulky HHDP (or DHHDP) group; thus, it is considered as a safe and effective ferroptosis‐inhibitor. Ferroptosis inhibitors: Geraniin can inhibit ferroptosis in mesenchymal stem cells. The inhibitory effect is attributed to the polyphenolic structures, especially hexahydroxydiphenoyl and dehydrohexahydroxydiphenoyl groups. The two bulky groups hinder radical‐adduct formation, meaning that geraniin ferroptosis‐inhibitor cannot cause cross‐adduct with biomolecules. Geraniin and ellagitannins have been found to be safe and effective ferroptosis‐inhibitors.