biostudies-literatureZhu YGreat Ormond Street Hospital CharityGreat Ormond Street Hospital Charity (GOSH)Takeda Science FoundationMedical Research CouncilNational Institute for Health Research (NIHR)UK Dementia Research Institute The National Institute for Health Research Cambridge Biomedical Research Centre at Addenbrooke’s Hospital542-551https://www.ebi.ac.uk/biostudies/studies/S-EPMC11021183biostudies-literatureUnknown26(4)β-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway. However, our data indicate that WIPI4 depletion causes ferroptosis-a type of cell death induced by lipid peroxidation-via an autophagy-independent mechanism, as demonstrated both in cell culture and in zebrafish. WIPI4 depletion increases ATG2A localization at endoplasmic reticulum-mitocNature cell biologyLoss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.PMC11021183N/AUKDRI-2202Fujimaki MSnape LFleming ARubinsztein DCZhu YLopez AfalseLoss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.β-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway. However, our data indicate that WIPI4 depletion causes ferroptosis-a type of cell death induced by lipid peroxidation-via an autophagy-independent mechanism, as demonstrated both in cell culture and in zebrafish. WIPI4 depletion increases ATG2A localization at endoplasmic reticulum-mitoc2024-01-01T00:00:00Z2024 Apr2026-06-01T20:23:30.594Z2025-04-06T00:46:44.665ZS-EPMC110211833845405010.1038/s41556-024-01373-3