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–mitochondrial contact sites, which enhances phosphatidylserine import into mitochondria. This results in increased mitochondrial synthesis of phosphatidylethanolamine, a major lipid prone to peroxidation, thus enabling ferroptosis. This mechanism has minimal overlap with classical ferroptosis stimuli but provides insights into the causes of neurodegeneration in BPAN and may provide clues for therapeutic strategies.

β-螺旋桨蛋白相关神经变性 (BPAN) 是一种罕见的 X 连锁显性疾病，是表现为神经变性和脑铁积累的几种疾病之一。编码 WIPI4 的WD 重复结构域 45 ( WDR45 ) 基因突变导致 BPAN 功能丧失，但这些触发病理学的细胞机制尚不清楚。文献中普遍认为，鉴于 WIPI4 在该降解途径中发挥作用，BPAN 只是自噬缺陷的结果。然而，我们的数据表明，WIPI4 耗尽会通过一种不依赖于自噬的机制导致铁死亡（一种由脂质过氧化诱导的细胞死亡），这一点在细胞培养物和斑马鱼中都得到了证明。WIPI4 缺失增加了 ATG2A 在内质网-线粒体接触位点的定位，从而增强了磷脂酰丝氨酸向线粒体的输入。这导致线粒体合成磷脂酰乙醇胺（一种容易过氧化的主要脂质）增加，从而导致铁死亡。这种机制与经典的铁死亡刺激几乎没有重叠，但提供了对 BPAN 神经变性原因的深入了解，并可能为治疗策略提供线索。