Inducing potent ferroptosis in cancer cells by manipulation of ferritinophagy with a ferritin-targeted ATTEC

Leveraging dysregulated iron metabolism offers a promising strategy to selectively induce Ferroptosis in Cancer cells; however, it still faces the challenge of insufficient elevation of the labile iron pool (LIP). In this study, we presented a novel approach to effectively liberate endogenous Fe²⁺ and induce potent Ferroptosis in Cancer cells by regulation ferritinophagy with a ferritin-targeted autophagosome-tethering compounds (ATTEC) of 16AA-C₁₀-DPC. The ferritin-binding peptide (16AA) derived from nuclear receptor coactivator 4 (NCOA4) accounted for binding with the ferritin heavy chain (FTH1), while DPC, 5,7-dihydroxy-4-phenylcoumarin, was a LC3-binding warhead facilitating the autophagosomes recruitment. To improve cellular uptake efficiency, the chimera was integrated with the pH-responsive mPEG₂₀₀₀-PLA-pHis₁₀ copolymer, forming the nanocomplexes of 16AA-C₁₀-DPC@PPH. After endocytosis and translocation to cytoplasm, the ATTEC induced ferritinophagy process by selectively degrading ferritin via autophagy-lysosome pathway, releasing the abundantly stored endogenous Fe²⁺ and H₂O₂ for catalyzing Fenton reaction and lipid peroxidization cascades. Together, manipulation of ferritinophagy has been demonstrated to be effective in utilization of dysregulated iron metabolism to overcome Ferroptosis defense mechanisms, subsequently inducing potent ferroptotic Cancer cell death.

ATTEC; Dysregulated iron metabolism; Ferritin targeted degradation; Ferritinophagy; Ferroptosis.