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<p>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.</p> Graphical Abstract <p>In neonatal HIE, ferroptosis involves iron overload, lipid peroxidation, GPX4 suppression, and activation of TLR4/NF-κB and ER stress, alongside Nrf2 inhibition. VD/VDR signaling activates Nrf2/HO-1, restores GPX4, regulates iron/lipid metabolism, and reduces neuroinflammation—attenuating ferroptosis and promoting neuroprotection.</p> <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Yueju Cai,
  • Wei Zhou

摘要

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.

Graphical Abstract

In neonatal HIE, ferroptosis involves iron overload, lipid peroxidation, GPX4 suppression, and activation of TLR4/NF-κB and ER stress, alongside Nrf2 inhibition. VD/VDR signaling activates Nrf2/HO-1, restores GPX4, regulates iron/lipid metabolism, and reduces neuroinflammation—attenuating ferroptosis and promoting neuroprotection.