Sci Rep. 2026 May 30. doi: 10.1038/s41598-026-54865-7. Online ahead of print.
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.
PMID:42218217 | DOI:10.1038/s41598-026-54865-7