Glibenclamide attenuates neuronal pyroptosis by modulating KATP channels in the hippocampus of palmitic acid-induced lipotoxic mice

Metabolic lipotoxicity contributes to neuroinflammation and cognitive dysfunction, yet the cellular mechanisms linking saturated fatty acids to hippocampal injury remain incompletely understood. In this study, we investigated whether glibenclamide (GB), a clinically used ATP-sensitive potassium (K ATP ) channel inhibitor, modulates hippocampal inflammatory responses induced by palmitic acid (PA). Male C57BL/6N mice were subjected to chronic PA injections with or without GB treatment for four weeks. Behavioral tests, histological analyses, and molecular assays were performed to evaluate hippocampal function and inflammatory signaling. Chronic PA exposure impaired recognition memory and was associated with neuronal apoptosis, microglial activation, and lipid accumulation in the hippocampus. PA treatment also increased the expression of inflammasome-associated markers, including NLRP3, caspase-1, gasdermin D (GSDMD), and IL-1β, together with elevated levels of pro-inflammatory cytokines (IL-6, MCP-1, TNF-α). GB treatment attenuated these changes and reduced markers of inflammasome activation in both hippocampal tissue and PA-treated BV2 microglial cells. Immunofluorescence analysis further revealed spatial proximity between SUR1/K ATP channel components and GSDMD at the microglial cell surface following PA exposure. These findings indicate that PA-induced lipotoxic stress promotes microglial activation and inflammasome-associated pyroptotic signaling in the hippocampus. GB treatment mitigates these inflammatory responses, suggesting that modulation of microglial signaling pathways may represent a potential strategy for metabolic disorder–associated cognitive dysfunction. • Palmitic acid induces hippocampal dysfunction via microglial K ATP activation. • PA triggers NLRP3/caspase-1/GSDMD-mediated pyroptosis and neuronal loss. • Glibenclamide reduces lipid accumulation, cytokine release, and pyroptosis. • GB preserves hippocampal neurons and restores cognitive performance • Microglial K ATP channels are potential therapeutic targets in neurodegeneration.