Molecular mechanisms of FSP1-regulated ferroptosis and therapeutic implications in various cancers.

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In addition to the canonical glutathione peroxidase 4 pathway, ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondria-associated 2, functions as a major glutathione-independent suppressor of ferroptosis. Current evidence indicates that FSP1 restrains lipid peroxidation mainly through the nicotinamide adenine dinucleotide (phosphate) [NAD(P)H]-dependent coenzyme Q10 axis. FSP1 has also been implicated in the noncanonical vitamin K cycle, which further expands its redox role. Emerging studies suggest that liquid-liquid phase separation and membrane repair may broaden the functional landscape of FSP1, although these mechanisms remain less fully defined. We then summarize the multilayer regulation of FSP1 and discuss how it contributes to ferroptosis resistance, tumor adaptation, and therapeutic responses in cancer. Finally, we review current preclinical efforts to target FSP1, with emphasis on small-molecule inhibitors, mechanism-based combinations, candidate biomarkers, and major translational challenges. Together, these observations position FSP1 as an important determinant of ferroptosis resistance in cancer and a promising focus for further mechanistic and translational study.