Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition

Ferroptosis, a distinctive form of programmed cell death,
has been
implicated in numerous pathological conditions, and its inhibition
is considered a promising therapeutic strategy. Currently, there is
a scarcity of efficient antagonists for directly regulating intracellular
ferrous iron. Ferritinophagy, an essential process for supplying intracellular
labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective
autophagy receptor for the ferritin iron storage complex, thus playing
a pivotal role in ferritinophagy. In this study, we reported a novel
von Hippel–Lindau-based NCOA4 degrader, V3, as
a potent ferroptosis inhibitor with an intracellular ferrous iron
inhibition mechanism. V3 significantly reduced NCOA4
levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by
multiple pathways within cells and alleviating liver damage. This
research presents a chemical knockdown tool targeting NCOA4 for further
exploration into intracellular ferrous iron in ferroptosis, offering
a promising therapeutic avenue for ferroptosis-related acute liver
injury.