Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Induction of ferroptosis emerges as an effective methodfor cancertreatment. With massive efforts to elucidate the ferroptosis mechanism,the development of new ferroptosis inducers proceeds rather slowly,with only a few small molecules identified. Herein, we report ourdiscovery of marine alkaloid lepadins E and H as a new class of ferroptosisinducers. Our in vitro studies show that lepadins E and H exhibitsignificant cytotoxicity, promote p53 expression, increase ROS productionand lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulateACSL4 expression, all of which consistently support induction of ferroptosisthrough the classical p53-SLC7A11-GPX4 pathway. Our animal model studyof lepadin H confirms its in vivo antitumor efficacy with negligibletoxicity to normal organs. This work elucidates the mode of actionof lepadins (E and H) and verifies their in vivo efficacy as a newclass of ferroptosis inducers for anticancer therapy with translationalpotential.

Automated summary

Induction of ferroptosis has been found to be an effective method for cancer treatment. In this study, marine alkaloid lepadins E and H were discovered as new ferroptosis inducers. In vitro experiments showed that lepadins E and H exhibited significant cytotoxicity and induced ferroptosis through the p53-SLC7A11-GPX4 pathway. Animal model studies further confirmed their in vivo antitumor efficacy. This discovery highlights the potential of lepadins as a new class of ferroptosis inducers for anticancer therapy.