Apoptosis-inducing factor 2 (AIFM2)

Apoptosis-inducing factor 2 (AIFM2), also known as Ferroptosis suppressor protein 1 (FSP1), is a flavoprotein oxidoreductase encoded by the AIFM2 gene on human chromosome 10[1][2][3]. Initially characterized as a pro-apoptotic factor due to its homology to AIF (apoptosis-inducing factor), AIFM2's principal established role is now as a strong suppressor of ferroptosis—a non-apoptotic, iron-dependent form of cell death caused by lipid peroxidation. FSP1 achieves this by using NAD(P)H to reduce ubiquinone (coenzyme Q10), vitamin E, and vitamin K to their antioxidant forms, halting the propagation of lipid peroxides in cell membranes[2][3][4][5]. AIFM2 is localized to the cytosol and mitochondrial membrane but lacks a canonical mitochondrial targeting sequence. Its anti-ferroptotic function is crucial for cell survival under oxidative stress and is independent of the glutathione peroxidase 4 (GPX4) pathway, representing a parallel antioxidant system[1][3][4]. AIFM2 is highly relevant in cancer, where high FSP1 expression confers resistance to ferroptosis-inducing therapies, including GPX4 inhibition; thus, pharmacological inhibitors of FSP1 (such as icFSP1) are under research as potential sensitizers in cancer treatments[3][5]. Downregulation or loss of AIFM2 has also been observed in several tumor types[1]. Beyond oncology, its role in infection, metabolism, and neuroprotection is also under active investigation[1][5].

Other names

Ferroptosis suppressor protein 1FSP1AMIDPRG3p53-responsive gene 3 proteinApoptosis-inducing factor-homologous mitochondrion-associated inducer of deathApoptosis-inducing factor mitochondria associated 2FLJ14497

Inhibition of AIFM2/FSP1 promotes ferroptosis by preventing the regeneration of antioxidant ubiquinol from ubiquinone, thereby increasing lipid peroxidation and cell death. Activation or overexpression of FSP1 blocks ferroptosis and protects against oxidative cell death independent of glutathione peroxidase 4 (GPX4).