Identification\nof Isoliensinine as a Ferroptosis Suppressor\nwith Iron-Chelating Activity

Ferroptosis\nis a type of regulated cell death driven\nby the iron-dependent\naccumulation of lipid peroxides. The high involvement of ferroptosis\nin diverse human diseases highlights the need for the identification\nof new chemotypes with anti-ferroptotic activity. Here, we performed\na natural product library screening in HT1080 fibrosarcoma cells and\nidentified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine\n(ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically,\nferroptosis resistance conferred by these compounds is mainly through\nGPX4/NRF2-independent mechanisms. Among them, only ISL could effectively\nrescue ferroptosis induced by FINO<sub>2</sub>, which is a stable\noxidant of ferrous iron, suggesting that ISL may have the properties\nof an iron chelator. Consistent with the hypothesis, both computational\ntools and X-ray photoelectron spectroscopy supported the binding between\nISL and iron ions. And ISL greatly inhibited excessive iron-dependent\nferroptotic cell death through limiting intracellular iron accumulation.\nFurthermore, its iron chelator activity also protected mice from organ\ninjury in an acute iron overload model. In conclusion, this study\nprovided valuable insights for developing effective anti-ferroptosis\nagents from natural products, which represent a potential therapeutic\nstrategy for treating ferroptosis-associated organ damage.