Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Induction of ferroptosis emerges as an effective method
for cancer
treatment. 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 our
discovery of marine alkaloid lepadins E and H as a new class of ferroptosis
inducers. Our in vitro studies show that lepadins E and H exhibit
significant cytotoxicity, promote p53 expression, increase ROS production
and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate
ACSL4 expression, all of which consistently support induction of ferroptosis
through the classical p53-SLC7A11-GPX4 pathway. Our animal model study
of lepadin H confirms its in vivo antitumor efficacy with negligible
toxicity to normal organs. This work elucidates the mode of action
of lepadins (E and H) and verifies their in vivo efficacy as a new
class of ferroptosis inducers for anticancer therapy with translational
potential.