Fig. 6. Mechanistic insights into FSP1 and its different target sites using FSP1 inhibitors.

The chemical approach using the compound library and the genetic approach using targeted and untargeted mutagenesis uncover the mechanism of action of two representative FSP1 inhibitors. Human-specific iFSP1 targets the quinone-binding pocket, whereas species-independent viFSP1 targets the NAD(P)H-binding pocket. Besides, a well-conserved proton transfer function is critical for the anti-ferroptotic activity of FSP1.