{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:16:38Z","timestamp":1793063798985,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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 (ROR\u03b1) modulates mitophagy to suppress mtDNA-cGAS-STING-NLRP3 signaling in aging microglia, offering therapeutic potential for HIE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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 ROR\u03b1 as a pivotal regulator.\n                      <jats:italic>In vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      HIE models with ROR\u03b1 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Multi-omics integration revealed ROR\u03b1 as a hub gene linked to inflammatory and metabolic pathways. ROR\u03b1 activation enhanced mitophagy, reducing mtDNA leakage by 43% and cGAS-STING activity by 68%, which suppressed NLRP3 inflammasome activation (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.01). This correlated with improved cognitive\/motor function in HIE rats (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.05) and attenuated ROS\/IL-1\u03b2 levels. Critically, 3-MA reversed ROR\u03b1\u2019s anti-inflammatory effects, confirming mitophagy dependence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ROR\u03b1 alleviates HIE by resolving microglial neuroinflammation through mitophagic inhibition of mtDNA-cGAS-STING-NLRP3 signaling. These findings position ROR\u03b1 as a novel therapeutic target for HIE, bridging mitochondrial quality control and neuroimmunology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1592737","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T12:44:26Z","timestamp":1753793066000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["ROR\u03b1-activated mitophagy attenuating hypoxic-ischemic encephalopathy via suppression of microglial cGAS-STING 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