Maresin-1 alleviates lipid peroxidation-induced ferroptosis after radiation-induced brain injury in mice through the RORα/NRF2 pathway

Exp Neurol. 2025 Jul:389:115258. doi: 10.1016/j.expneurol.2025.115258. Epub 2025 Apr 14.

Abstract

Ferroptosis plays a critical role in radiation-induced brain injury (RIBI). The role of Maresin-1, which has anti-inflammatory and antiferroptotic properties, in RIBI is still unclear. This study aimed to explore the effects and mechanisms of Maresin-1 on ferroptosis after RIBI in mice. A mouse model of RIBI was constructed through whole-brain irradiation. Short-term neurological functions were evaluated by the modified Garcia score and the beam balance score, and long-term neurological functions were evaluated by the Morris water maze and the rotarod test. Changes in the number of NeuN-positive neurons were detected through immunohistochemistry. The lipid peroxidation level was evaluated by detecting the contents of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), glutathione-reduced (GSH) and glutathione-oxidized (GSSG). The expression of the ferroptosis-related markers glutathione peroxidase 4 (GPX4) and cyclooxygenase 2 (COX2) was assessed via Western blotting. Adeno-associated viruses were used to knock down retinoic acid receptor-related orphan receptor alpha (RORα) or nuclear factor erythroid 2-related factor 2 (NRF2) to explore the mechanism by which Maresin-1 alleviates ferroptosis. The results showed that Maresin-1 could significantly reduce the levels of MDA, 4-HNE, GSSG, and COX2 after RIBI; increase the contents of GSH and GPX4; reduce neuronal loss in the cortex and hippocampus; and improve the short-term and long-term neurological functions of mice. After the knockdown of RORα or NRF2, the protective effects of Maresin-1 in mediating anti-lipid peroxidation and anti-ferroptosis were abolished. Our study revealed that Maresin-1 partially alleviates lipid peroxidation-induced ferroptosis after RIBI in mice via the RORα and NRF2 pathways, improving their neurological functions. This study highlights the protective role of Maresin-1 in RIBI and provides a feasible therapeutic strategy for subsequent in-depth research and clinical intervention.

Keywords: Ferroptosis; Lipid peroxidation; Maresin-1; RORα; Radiation-induced brain injury.

MeSH terms

  • Animals
  • Brain Injuries* / drug therapy
  • Brain Injuries* / etiology
  • Brain Injuries* / metabolism
  • Docosahexaenoic Acids* / pharmacology
  • Docosahexaenoic Acids* / therapeutic use
  • Ferroptosis* / drug effects
  • Ferroptosis* / physiology
  • Ferroptosis* / radiation effects
  • Lipid Peroxidation* / drug effects
  • Lipid Peroxidation* / physiology
  • Lipid Peroxidation* / radiation effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2* / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 1* / metabolism
  • Radiation Injuries, Experimental* / drug therapy
  • Radiation Injuries, Experimental* / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Docosahexaenoic Acids
  • Nfe2l2 protein, mouse
  • NF-E2-Related Factor 2
  • 7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Rora protein, mouse