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Background <p>In Parkinson’s disease (PD), microglial activation is driven by metabolic reprogramming toward aerobic glycolysis, a shift regulated by pyruvate kinase M2 (PKM2). While the environmental toxin rotenone is a recognized PD risk factor, the precise glycolytic mechanism linking it to microglial neuroinflammation remains unclear, and the therapeutic potential of targeting this axis is largely unexplored.</p> Purpose <p>We sought to elucidate the specific glycolytic pathway by which rotenone induces microglial activation and to investigate whether shikonin, a natural PKM2 inhibitor, could attenuate neuroinflammation by targeting this metabolic mechanism.</p> Methods <p>Using rotenone (250 nM)-treated BV2 microglia, we assessed glycolytic function (lactate production, glucose consumption) and quantified the formation of methylglyoxal-derived hydroimidazolones (MG-Hs), key pro-inflammatory glycation adducts. NF-κB pathway activation and inflammatory cytokine release were evaluated. The inhibitory effects of shikonin on this cascade were systematically examined.</p> Results <p>We identified a novel mechanistic pathway: rotenone promotes PKM2-mediated glycolytic flux, leading to accumulation of the cytotoxic metabolite methylglyoxal (MG) and its derived MG-Hs. These MG-Hs function as critical signaling mediators that directly activate the NF-κB pathway, fueling neuroinflammation. Shikonin effectively disrupted this cascade at its source by inhibiting PKM2, thereby normalizing glycolytic activity, reducing MG-Hs formation, and subsequently suppressing NF-κB activation and the release of pro-inflammatory factors.</p> Conclusion <p>This study delineates a complete PKM2-glycolysis-MG-Hs-NF-κB axis as a fundamental mechanism in rotenone-induced neuroinflammation. Our results provide compelling preclinical evidence that shikonin exerts its neuroprotective effects by specifically targeting this metabolic-inflammatory pathway, positioning it as a highly promising disease-modifying therapeutic candidate for PD.</p>

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Shikonin alleviates rotenone-induced Parkinson’s disease neuroinflammation by targeting PKM2-mediated glycolytic MG-Hs production

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Ya Zhao,
  • Dan Wang,
  • Dan Mu,
  • Lang Qu,
  • Rong Li

摘要

Background

In Parkinson’s disease (PD), microglial activation is driven by metabolic reprogramming toward aerobic glycolysis, a shift regulated by pyruvate kinase M2 (PKM2). While the environmental toxin rotenone is a recognized PD risk factor, the precise glycolytic mechanism linking it to microglial neuroinflammation remains unclear, and the therapeutic potential of targeting this axis is largely unexplored.

Purpose

We sought to elucidate the specific glycolytic pathway by which rotenone induces microglial activation and to investigate whether shikonin, a natural PKM2 inhibitor, could attenuate neuroinflammation by targeting this metabolic mechanism.

Methods

Using rotenone (250 nM)-treated BV2 microglia, we assessed glycolytic function (lactate production, glucose consumption) and quantified the formation of methylglyoxal-derived hydroimidazolones (MG-Hs), key pro-inflammatory glycation adducts. NF-κB pathway activation and inflammatory cytokine release were evaluated. The inhibitory effects of shikonin on this cascade were systematically examined.

Results

We identified a novel mechanistic pathway: rotenone promotes PKM2-mediated glycolytic flux, leading to accumulation of the cytotoxic metabolite methylglyoxal (MG) and its derived MG-Hs. These MG-Hs function as critical signaling mediators that directly activate the NF-κB pathway, fueling neuroinflammation. Shikonin effectively disrupted this cascade at its source by inhibiting PKM2, thereby normalizing glycolytic activity, reducing MG-Hs formation, and subsequently suppressing NF-κB activation and the release of pro-inflammatory factors.

Conclusion

This study delineates a complete PKM2-glycolysis-MG-Hs-NF-κB axis as a fundamental mechanism in rotenone-induced neuroinflammation. Our results provide compelling preclinical evidence that shikonin exerts its neuroprotective effects by specifically targeting this metabolic-inflammatory pathway, positioning it as a highly promising disease-modifying therapeutic candidate for PD.