FSP1

FSP1, or ferroptosis suppressor protein 1, is a cytosolic oxidoreductase that inhibits ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. In humans the protein is encoded by the AIFM2 gene and is a member of the apoptosis-inducing factor (AIF) family. FSP1 provides a glutathione-independent defense against ferroptosis and operates in parallel with GPX4, the classic ferroptosis gatekeeper.

Mechanism and localization: FSP1 is anchored to cellular membranes, notably the plasma membrane, through an N-terminal motif that supports myristoylation. It uses NAD(P)H to reduce ubiquinone (CoQ) to ubiquinol (CoQH2). CoQH2 then acts as a lipid-soluble radical-trapping antioxidant that halts lipid peroxidation in membranes, thereby preventing ferroptotic death. This CoQ-based lipid antioxidant system complements the GPX4-glutathione pathway in protecting cells from ferroptosis.

Genetics and literature: The FSP1 protein is encoded by the AIFM2 gene and is part of the broader AIFM family. Its discovery highlighted a GPX4-independent ferroptosis defense mechanism, expanding understanding of cellular redox biology and ferroptosis regulation. FSP1 activity can influence cellular sensitivity to ferroptosis inducers and interacts with other ferroptosis pathways to determine cell fate.

Clinical and research implications: In cancer and other diseases, upregulation of FSP1 can confer resistance to ferroptosis-inducing therapies, making it a potential target for modulating treatment responses. Conversely, loss or inhibition of FSP1 can increase susceptibility to ferroptosis, particularly when GPX4 pathways are compromised. Ongoing research seeks to clarify tissue-specific roles and therapeutic potential of modulating the FSP1-CoQ axis.