Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder lacking disease-modifying therapies. Rotenone (Rot) is widely used to model PD, but its neurotoxicity is not fully understood beyond mitochondrial complex I inhibition. Here, we identify a glycolytic mechanism that contributes to Rot-induced neuronal damage downstream of complex I inhibition. Our in vitro data demonstrate that Rot enhances glycolytic flux, leading to accumulation of methylglyoxal-derived hydroimidazolones (MG-Hs), which drive irreversible cellular damage. Shikonin effectively attenuates Rot-induced apoptosis by inhibiting PKM2, thereby suppressing glycolysis and reducing MG-Hs formation. In a rat model, shikonin robustly improves motor function and preserves nigrostriatal dopaminergic neurons. Collectively, our findings reveal a previously unrecognized glycolytic-mediated pathway involving PKM2-driven glycolysis and MG-Hs accumulation that contributes to rotenone neurotoxicity alongside mitochondrial dysfunction, and highlight shikonin as a promising neuroprotective agent for Parkinson’s disease intervention.
Funding
This work was supported by Sichuan Science and Technology Program (2024YFFK0169), the Natural Science Foundation of Sichuan Province (2024NSFSC1731, 2025ZNSFSC0894), the Health Commission of Sichuan Province Medical Science and Technology Program (24WXXT13), the Open Fund of Key Laboratory of Preclinical Study for New Drugs of Gansu Province (GSKFKT-2301) and the Doctoral Scientific Research Fund of North Sichuan Medical College (CBY23-QDA05, CBY24-QDA01, CBY24-QDA03, CBY24-QDA05).
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The permission of animal use were approved by the Institutional Animal Care and Use Committee of North Sichuan Medical College (approval number NSMC 2024108) and conducted in accordance with ARRIVE guidelines 2.0 and the NIH Guide for the Care and Use of Laboratory Animals. All animal experiments strictly complied with the institutional pain management protocols, and pre-defined study endpoints and humane endpoints were strictly implemented to ensure the welfare of experimental animals.
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Li, R., Ma, J.W., Chen, H. et al. PKM2-driven glycolysis mediates rotenone neurotoxicity via MG-Hs in Parkinson’s disease. Sci Rep (2026). https://doi.org/10.1038/s41598-026-54865-7
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DOI: https://doi.org/10.1038/s41598-026-54865-7
