Rutin ameliorates perioperative neurocognitive disorders by inhibiting microglial HIF-1α/PKM2‑driven glycolysis.
BACKGROUND Perioperative neurocognitive disorders (PND) are common complications in elderly patients, largely driven by microglia-mediated neuroinflammation. Rutin, a natural flavonoid, exhibits anti-inflammatory and neuroprotective effects, but its role in PND remains unclear. METHODS An abdominal surgery-induced PND model was established in aged mice. Behavioral performance was assessed using the Morris Water Maze and Fear Conditioning Test. Hippocampal tissues were collected to evaluate microglial activation, synaptic integrity, and neuroinflammatory markers. Glycolytic metabolism was assessed by measuring lactate levels and expression of glycolysis-related genes and proteins (HIF-1α, PKM2). In vitro studies using LPS-stimulated BV2 microglial cells were performed to validate the metabolic regulatory effects of rutin, including Seahorse analysis of glycolytic flux and HIF-1α overexpression. RESULTS Surgery-induced cognitive impairment was associated with robust microglial activation, synaptic loss, and increased hippocampal expression of HIF-1α and PKM2. Rutin treatment significantly improved cognitive performance, attenuated microglial pro-inflammatory polarization, restored synaptic protein expression, and reduced neuroinflammation. Mechanistically, rutin suppressed glycolytic activity in vivo and in vitro, as evidenced by decreased lactate production, reduced glycolytic gene expression, and normalized extracellular acidification rates. The anti-glycolytic and anti-inflammatory effects of rutin in microglia were partially reversed by HIF-1α overexpression. CONCLUSION Rutin alleviates surgery-induced cognitive impairment by inhibiting microglial glycolytic reprogramming via the HIF-1α/PKM2 pathway. These findings identify microglial immunometabolism as a therapeutic target in PND and position rutin as a promising candidate for neuroprotection in the perioperative setting.