Ferroptosis in Neonatal Hypoxic-Ischemic Encephalopathy: Mechanisms and the Therapeutic Potential of Vitamin D/VDR Signaling

Abstract

As a major neonatal brain disorder, hypoxic-ischemic encephalopathy(HIE) presents with elevated risks of long-term disability and neonatal death. Ferroptosis is a distinct mode of regulated cell death marked by excess intracellular iron, oxidative lipid injury, and suppressed GPX4 activity, and has gained attention as a pivotal mechanism in the development of HIE. Signaling pathways such as Nrf2, TLR4/NF-κB, and endoplasmic reticulum stress(ERS) play critical roles.Vitamin D (VD) and its receptor (VDR), beyond their classical roles in calcium-phosphate homeostasis, as neuroprotective modulators of ferroptosis. VD/VDR signaling promotes antioxidant defenses (e.g., via the Nrf2/HO-1 pathway), restores GPX4 activity, regulates iron and lipid metabolism, and mitigates neuroinflammation.These insights provide a rationale for exploring VD/VDR-based interventions as adjunctive strategies to therapeutic hypothermia, which could potentially be explored to improve neurodevelopmental outcomes in affected neonates.