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<p>Clinical evidence points to the Traditional Chinese Medicine Fuzheng Huayu recipe (FZHYR) as an anti-fibrosis drug. Our previous studies have shown that FZHYR regulates macrophage polarization and the expression of NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2 (NDUFA2) to inhibit pulmonary fibrosis. This study aims to explore the mechanism of FZHYR regulates macrophage polarization and NDUFA2 expression in the treatment of pulmonary fibrosis. NR8383 alveolar macrophages polarizing to M1 or M2 polarization by stimulation with LPS/IFN-γ or IL-14/IL-13 and received FZHYR treatment. Macrophage polarization was verified by detecting the levels of transmembrane protein that specific expression using flow cytometry and levels of inflammatory factors. Oxidative phosphorylation change was reflected by mitochondrial ROS and oxygen consumption rate. The effect of FZHYR on m6A of <i>Ndufa2</i> mRNA and the involvement of m6A modification enzymes (METTL3 and IGF2BP1) was investigated. FZHYR promoted macrophage M1 polarization and inhibited macrophage M2 polarization. FZHYR inhibited oxidative phosphorylation and NDUFA2 expression in M2 macrophages. <i>Ndufa2</i> silencing inhibited macrophage M2 polarization and oxidative phosphorylation. M2 macrophage polarization and oxidative phosphorylation induced by <i>Ndufa2</i> overexpression were reversed by FZHYR. Mechanistically, METTL3 induced <i>Ndufa2</i> m6A methylation in an IGF2BP1-dependent manner in FZHYR-treated M2 macrophage. Moreover, the inhibition of METTL3 suppressed macrophage M2 polarization and oxidative phosphorylation. FZHYR inhibits M2 macrophage polarization through the inhibition of METTL3-mediated m6A modification and downregulation of NDUFA2 and oxidative phosphorylation.</p>

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Fuzheng Huayu recipe inhibits alveolar macrophage M2 polarization and oxidative phosphorylation via METTL3-mediated NDUFA2 m6A modification

  • 期刊论文

  • 发表日期：

    2025年9月20日

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  • Yucen Sun,
  • Xinghua Yuan,
  • Weiling Huang,
  • Qiuhong Li,
  • Shanfang Zhang,
  • Yu Hang,
  • Jingyi Huang,
  • Jiaqi Li,
  • Yechang Qian,
  • Wei Zhang,
  • Li Li

摘要

Clinical evidence points to the Traditional Chinese Medicine Fuzheng Huayu recipe (FZHYR) as an anti-fibrosis drug. Our previous studies have shown that FZHYR regulates macrophage polarization and the expression of NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2 (NDUFA2) to inhibit pulmonary fibrosis. This study aims to explore the mechanism of FZHYR regulates macrophage polarization and NDUFA2 expression in the treatment of pulmonary fibrosis. NR8383 alveolar macrophages polarizing to M1 or M2 polarization by stimulation with LPS/IFN-γ or IL-14/IL-13 and received FZHYR treatment. Macrophage polarization was verified by detecting the levels of transmembrane protein that specific expression using flow cytometry and levels of inflammatory factors. Oxidative phosphorylation change was reflected by mitochondrial ROS and oxygen consumption rate. The effect of FZHYR on m6A of Ndufa2 mRNA and the involvement of m6A modification enzymes (METTL3 and IGF2BP1) was investigated. FZHYR promoted macrophage M1 polarization and inhibited macrophage M2 polarization. FZHYR inhibited oxidative phosphorylation and NDUFA2 expression in M2 macrophages. Ndufa2 silencing inhibited macrophage M2 polarization and oxidative phosphorylation. M2 macrophage polarization and oxidative phosphorylation induced by Ndufa2 overexpression were reversed by FZHYR. Mechanistically, METTL3 induced Ndufa2 m6A methylation in an IGF2BP1-dependent manner in FZHYR-treated M2 macrophage. Moreover, the inhibition of METTL3 suppressed macrophage M2 polarization and oxidative phosphorylation. FZHYR inhibits M2 macrophage polarization through the inhibition of METTL3-mediated m6A modification and downregulation of NDUFA2 and oxidative phosphorylation.