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<p>Microglia play a pivotal role in neuroinflammation, and targeting their activation has emerged as a promising therapeutic strategy for brain injury. Oxymatrine (OMT) exhibits anti-inflammatory and neuroprotective properties;&#xa0;however, whether OMT regulates microglial M1/M2 polarization via epigenetic mechanisms, particularly RNA N6-methyladenosine (m<sup>6</sup>A) modification, remains unknown. Moreover, the molecular link between m<sup>6</sup>A demethylase FTO and the metabolic regulator PGC-1α in microglial polarization has not been explored.&#xa0;In this study, we investigated the effects of OMT on microglial M1/M2 polarization using an oxygen–glucose deprivation/reperfusion (OGD/R)-induced neuroinflammation model in primary murine microglia.&#xa0;Our findings fill this gap by demonstrating for the first time that OMT attenuates OGD/R-induced neuroinflammation by promoting a shift from the M1 to the M2 phenotype. Mechanistically, this effect was associated with increased expression of fat mass and obesity-associated protein (FTO), which mediated OMT-driven M2 polarization via m6A-dependent upregulation of PPAR-γ coactivator-1α (PGC-1α). Furthermore, the m<sup>6</sup>A reader protein YTHDF2 regulated PGC-1α mRNA stability, thereby facilitating OMT-induced M2 microglial reprogramming. Collectively, our findings identify the FTO/PGC-1α axis as a novel pathway through which OMT modulates microglial polarization,&#xa0;thus addressing the critical knowledge gap regarding OMT’s epigenetic mechanism in neuroinflammation and providing new therapeutic insights for the treatment of neuroinflammatory disorders.</p>

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Oxymatrine suppresses neuroinflammation via promoting microglial M2 polarization through FTO-dependent m6A demethylation of PGC-1α mRNA

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Ping Li,
  • Shengnan Zhang,
  • Fei Xia,
  • Yu Wan,
  • Jing Wang,
  • Mei Xue,
  • Jiansong Yin

摘要

Microglia play a pivotal role in neuroinflammation, and targeting their activation has emerged as a promising therapeutic strategy for brain injury. Oxymatrine (OMT) exhibits anti-inflammatory and neuroprotective properties; however, whether OMT regulates microglial M1/M2 polarization via epigenetic mechanisms, particularly RNA N6-methyladenosine (m6A) modification, remains unknown. Moreover, the molecular link between m6A demethylase FTO and the metabolic regulator PGC-1α in microglial polarization has not been explored. In this study, we investigated the effects of OMT on microglial M1/M2 polarization using an oxygen–glucose deprivation/reperfusion (OGD/R)-induced neuroinflammation model in primary murine microglia. Our findings fill this gap by demonstrating for the first time that OMT attenuates OGD/R-induced neuroinflammation by promoting a shift from the M1 to the M2 phenotype. Mechanistically, this effect was associated with increased expression of fat mass and obesity-associated protein (FTO), which mediated OMT-driven M2 polarization via m6A-dependent upregulation of PPAR-γ coactivator-1α (PGC-1α). Furthermore, the m6A reader protein YTHDF2 regulated PGC-1α mRNA stability, thereby facilitating OMT-induced M2 microglial reprogramming. Collectively, our findings identify the FTO/PGC-1α axis as a novel pathway through which OMT modulates microglial polarization, thus addressing the critical knowledge gap regarding OMT’s epigenetic mechanism in neuroinflammation and providing new therapeutic insights for the treatment of neuroinflammatory disorders.