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<p>Dihydromyricetin (DHM) inhibits the progression of neuroinflammation-related diseases. Here, we aimed to explore the effect of DHM on spinal cord injury (SCI). First, an SCI mouse model was established by external force injury and treated with DHM (150&#xa0;mg/kg) by gavage for 28&#xa0;days. The results showed that DHM alleviated neuronal injury and improved motor dysfunction in SCI mice. Moreover, DHM decreased the levels of pyroptosis-related proteins, such as IL-18, NLRP3, ASC, GSDMD, and Caspase-1, and upregulated the levels of oxidative stress-related proteins, such as SOD1 and HO-1, in SCI mice. Interestingly, DHM inhibited the stimulator of interferon gene (STING) protein expression in SCI mice. Next, microglia (BV-2 cells) were treated with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) to construct a cell model and pretreated with 100&#xa0;μM DHM for 24&#xa0;h. The results showed that DHM promoted the expression of autophagy-related proteins (Beclin1, VPS34, CTSD, and LC3II), inhibited oxidative stress and pyroptosisin H<sub>2</sub>O<sub>2</sub>-induced BV-2 cells. 3-MA, an inhibitor of autophagy, STING overexpression vectors, and small interfering RNAs were used to reverse the effect of DHM on H<sub>2</sub>O<sub>2</sub>-induced microglia. 3-MA counteracted the protective effect of DHM on H<sub>2</sub>O<sub>2</sub>-induced BV-2 cells. Silencing STING induced autophagy and inhibited oxidative stress and pyroptosis in H<sub>2</sub>O<sub>2</sub>-induced BV-2 cells; overexpression of STING promoted the phosphorylation of PI3K and AKT. 740 Y-P, an activator of PI3K, reversed the effects of STING silencing on H<sub>2</sub>O<sub>2</sub>-induced BV-2 cells. In conclusion, DHM inhibited pyroptosis and oxidative stress by upregulating STING-mediated autophagy, thus improving motor dysfunction in SCI mice.</p> Graphical Abstract <p>Schematic illustration of the proposed molecular mechanism highlights the role of dihydromyricetin (DHM) in the pathophysiology of SCI and subsequent motor function recovery. DHM enhances autophagy by promoting the activation of the STING-mediated PI3K/AKT signaling pathway. Then enhanced autophagy reduces oxidative stress and pyroptosis in microglia, alleviating pathological damage and facilitating motor function recovery after SCI.</p> <p></p>

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Dihydromyricetin (DHM) Inhibits Microglial Pyroptosis and Oxidative Stress After Spinal Cord Injury by Promoting STING-Mediated Autophagy

  • 期刊论文

  • 发表日期：

    2025年7月29日

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  • Ruyin Liu,
  • Zongjin Yue,
  • Jiaan Dong,
  • Cheng Zhang,
  • Chuanghao Guo,
  • Xinli Wang

摘要

Dihydromyricetin (DHM) inhibits the progression of neuroinflammation-related diseases. Here, we aimed to explore the effect of DHM on spinal cord injury (SCI). First, an SCI mouse model was established by external force injury and treated with DHM (150 mg/kg) by gavage for 28 days. The results showed that DHM alleviated neuronal injury and improved motor dysfunction in SCI mice. Moreover, DHM decreased the levels of pyroptosis-related proteins, such as IL-18, NLRP3, ASC, GSDMD, and Caspase-1, and upregulated the levels of oxidative stress-related proteins, such as SOD1 and HO-1, in SCI mice. Interestingly, DHM inhibited the stimulator of interferon gene (STING) protein expression in SCI mice. Next, microglia (BV-2 cells) were treated with hydrogen peroxide (H2O2) to construct a cell model and pretreated with 100 μM DHM for 24 h. The results showed that DHM promoted the expression of autophagy-related proteins (Beclin1, VPS34, CTSD, and LC3II), inhibited oxidative stress and pyroptosisin H2O2-induced BV-2 cells. 3-MA, an inhibitor of autophagy, STING overexpression vectors, and small interfering RNAs were used to reverse the effect of DHM on H2O2-induced microglia. 3-MA counteracted the protective effect of DHM on H2O2-induced BV-2 cells. Silencing STING induced autophagy and inhibited oxidative stress and pyroptosis in H2O2-induced BV-2 cells; overexpression of STING promoted the phosphorylation of PI3K and AKT. 740 Y-P, an activator of PI3K, reversed the effects of STING silencing on H2O2-induced BV-2 cells. In conclusion, DHM inhibited pyroptosis and oxidative stress by upregulating STING-mediated autophagy, thus improving motor dysfunction in SCI mice.

Graphical Abstract

Schematic illustration of the proposed molecular mechanism highlights the role of dihydromyricetin (DHM) in the pathophysiology of SCI and subsequent motor function recovery. DHM enhances autophagy by promoting the activation of the STING-mediated PI3K/AKT signaling pathway. Then enhanced autophagy reduces oxidative stress and pyroptosis in microglia, alleviating pathological damage and facilitating motor function recovery after SCI.