Identification of Benzofuro[2,3-<i>b</i>]pyridine Pseudonatural Product as a Novel Class of Ferritinophagy Inhibitors that Potently Suppress Ferroptosis

Ferroptosis is a form of regulated cell death mediated by iron-dependent phospholipid peroxidation. Pharmacological inhibition of ferroptosis has been considered a promising therapeutic approach for various diseases. In this study, by integrating pseudonatural concepts with our newly developed rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition methodology, we rapidly assembled diverse benzofuro[2,3-<i>b</i>]pyridine PNP derivatives and systematically evaluated their antiferroptotic activity. Among these compounds, <b>4k</b> exhibited significant activity in suppressing ferroptosis. We further elucidated that <b>4k</b> acts as a novel and specific inhibitor of ferritinophagy by targeting NCOA4 and disrupting its interaction with ferritin. Subsequent results demonstrated that <b>4k</b> effectively ameliorated ConA-induced acute liver injury. Collectively, our findings indicate that <b>4k</b>, featuring benzofuro[2,3-<i>b</i>]pyridine PNP scaffolds, acts as a selective inhibitor and could serve as a potential lead compound for further research. This work suggests that pharmacological targeting of the NCOA4-FTH1 interaction represents a promising intervention strategy for ferroptosis-related diseases.