Fatty acid-binding protein 5 is a functional biomarker and indicator of ferroptosis in cerebral hypoxia

Abstract The progression of human degenerative and hypoxic/ischemic diseases is accompanied by widespread cell death. One death process linking iron-catalyzed reactive species with lipid peroxidation is ferroptosis, which shows hallmarks of both programmed and necrotic death in vitro. While evidence of ferroptosis in neurodegenerative disease is indicated by iron accumulation and involvement of lipids, a stable marker for ferroptosis has not been identified. Its prevalence is thus undetermined in human pathophysiology, impeding recognition of disease areas and clinical investigations with candidate drugs. Here, we identified ferroptosis marker antigens by analyzing surface protein dynamics and discovered a single protein, Fatty Acid-Binding Protein 5 (FABP5), which was stabilized at the cell surface and specifically elevated in ferroptotic cell death. Ectopic expression and lipidomics assays demonstrated that FABP5 drives redistribution of redox-sensitive lipids and ferroptosis sensitivity in a positive-feedback loop, indicating a role as a functional biomarker. Notably, immunodetection of FABP5 in mouse stroke penumbra and in hypoxic postmortem patients was distinctly associated with hypoxically damaged neurons. Retrospective cell death characterized here by the novel ferroptosis biomarker FABP5 thus provides first evidence for a long-hypothesized intrinsic ferroptosis in hypoxia and inaugurates a means for pathological detection of ferroptosis in tissue.