Iron chelation targets lipid metabolism to reduce white matter injury in germinal matrix hemorrhage

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) leads to neural cell death and inflammation, resulting in white matter injury in premature infants. Here, we show that IVH-induced iron deposition, ferroptosis, myelination failure, and disruption in lipid and oxylipin metabolism are mitigated by iron chelation using deferoxamine. We also identify the specific lipid and oxylipin metabolites and enzymes dysregulated in IVH, which are rescued by deferoxamine treatment. Our findings reveal that IVH causes iron accumulation, ferroptosis, and apoptosis, and leads to gene enrichment that contributes to cell death and oxidative injury in premature rabbits and human infants. IVH activates phospholipases (PLA2) and lysophosphatidylcholine acyltransferase-3 (LPCAT3), elevating levels of polyunsaturated fatty acids, lysophospholipids, and triacylglycerols, which contribute to neural cell injury. Furthermore, IVH upregulates cyclooxygenase, lipoxygenase, and cytochrome-P450 enzymes, which increases oxylipin production, thereby exacerbating inflammation. Importantly, iron chelation using systemic deferoxamine reduces levels of cPLA2, LPCAT3, and oxylipin-generating enzymes, restoring levels of lysophospholipids, triacylglycerols, and oxylipins in kits with IVH. Consistently, deferoxamine treatment alleviates IVH-induced ferroptosis, inflammation, microglial lipid accumulation, myelination failure, and neurological dysfunction. The study identifies that iron-triggered enzymatic dysregulation of lipid and oxylipin metabolism increases the generation of oxylipins and pro-inflammatory lipid metabolites, contributing to white matter injury in IVH survivors. These effects are mitigated by iron chelation.