Metabolic networks supporting FSP1 function and their relevance in ferroptosis cell death

Ferroptosis, a unique form of cell death characterized by iron-dependent lipid peroxidation, has gained significant attention as a potential target for eradicating therapy-resistant tumors. Recent studies have identified the flavoprotein ferroptosis suppressor protein 1 (FSP1) as a crucial regulator of ferroptosis, alongside glutathione peroxidase-4 (GPX4). FSP1, an NADP(H)-dependent oxidoreductase enzyme, plays a protective role by reducing lipophilic radical-trapping molecules (such as coenzyme Q, vitamin E, and vitamin K) to prevent uncontrolled lipid peroxidation. In the present study, we employed CRISPR-Cas9-based screens using an FSP1-dependent cellular model to identify novel metabolic pathways essential for FSP1 function. Our findings establish vitamin B₂ (riboflavin) as a key modulator of the FSP1-antioxidant recycling pathway and reveal a previously unrecognized link between vitamin B2 metabolism and ferroptosis. Furthermore, we propose a rational strategy to target these pathways and sensitize cancer cells to ferroptosis, with implications for understanding the interaction between nutrients and their contributions to cellular antioxidant capacity.