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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Molecular Innate Immunity

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1592737

This article is part of the Research TopicExploring Microglial Diversity and Its Impact on Neurological DiseasesView all 3 articles

RORα-Activated Mitophagy Attenuating Hypoxic-Ischemic Encephalopathy via Suppression of Microglial cGAS-STING axis

Provisionally accepted
Lei  SongLei Song*Haiyan  ShenHaiyan ShenWeiyan  HongWeiyan HongHongyi  ZhangHongyi ZhangHongyi  LuHongyi Lu
  • Nantong First People’s Hospital, Nantong, China

The final, formatted version of the article will be published soon.

Objective: Hypoxic-ischemic encephalopathy (HIE) involves neuroinflammation driven by microglial activation, yet regulatory mechanisms remain poorly defined. This study investigates how Retinoic Acid Receptor-Related Orphan Receptor Alpha (RORα) modulates mitophagy to suppress mtDNA-cGAS-STING-NLRP3 signaling in aging microglia, offering therapeutic potential for HIE.Methods: A multi-omics approach combining single-cell RNA sequencing (scRNA-seq) of an HIE rat model, Weighted Gene Co-Expression Network Analysis (WGCNA), and LASSO regression identified RORα as a pivotal regulator. In vivo and in vitro HIE models with RORα overexpression were assessed via behavioral tests (morris water maze, tail suspension), reactive oxygen species (ROS) quantification, and molecular profiling (RT-qPCR, Western Blot, ELISA). Mitophagy inhibitor 3-MA was used to validate pathway dependence.Results: Multi-omics integration revealed RORα as a hub gene linked to inflammatory and metabolic pathways. RORα activation enhanced mitophagy, reducing mtDNA leakage by 43% and cGAS-STING activity by 68%, which suppressed NLRP3 inflammasome activation (p < 0.01). This correlated with improved cognitive/motor function in HIE rats (p < 0.05) and attenuated ROS/IL-1β levels. Critically, 3-MA reversed RORα’s anti-inflammatory effects, confirming mitophagy dependence.Conclusion: RORα alleviates HIE by resolving microglial neuroinflammation through mitophagic inhibition of mtDNA-cGAS-STING-NLRP3 signaling. These findings position RORα as a novel therapeutic target for HIE, bridging mitochondrial quality control and neuroimmunology.

Keywords: hypoxic-ischemic encephalopathy, RORα, mitophagy, ScRNA-seq, Neuroinflammation, cGAS-STING pathway, NLRP3 inflammasome

Received: 13 Mar 2025; Accepted: 08 Jul 2025.

Copyright: © 2025 Song, Shen, Hong, Zhang and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Lei Song, Nantong First People’s Hospital, Nantong, China

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