Ferroptosis suppressor protein 1 (FSP1)

Ferroptosis suppressor protein 1 (FSP1, formerly known as AIFM2) is a FAD-dependent oxidoreductase that protects cells from iron-dependent lipid peroxidation (ferroptosis) by catalyzing the reduction of ubiquinone (Coenzyme Q10) and vitamin K to their active antioxidant forms using NAD(P)H as an electron donor. This non-mitochondrial pathway operates in parallel to the canonical glutathione peroxidase 4 (GPX4)-based mechanism, maintaining cellular resistance to ferroptosis and sustaining antioxidant defenses at the plasma membrane. FSP1 inhibition sensitizes cancer cells to ferroptosis, providing a promising strategy for anti-tumor therapies, and its enzymatic activity also modulates vitamin K pharmacology, including resistance to warfarin. Structurally, FSP1 contains distinct domains for FAD- and NAD(P)H-binding and requires homodimerization for maximal activity. Drugs targeting FSP1 may synergize with other ferroptosis inducers but could carry the risk of collateral damage by promoting excessive cell death in non-target tissues.

Other names

Apoptosis-inducing factor mitochondrial 2 (AIFM2)Ferroptosis suppressive protein 1FSP1

Most inhibitors (FSEN1, iFSP1, viFSP1) bind to the NAD(P)H-binding or substrate pocket of FSP1 and block its oxidoreductase activity, thereby allowing lipid peroxidation and triggering ferroptosis in target cells. Synergistic effect when combined with GPX4 inhibitors or ferroptosis inducers such as RSL3 (i.e., promotes cell death by blocking both FSP1 and GPX4-dependent antioxidant pathways).