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Overdose Propofol Emulsion-induced PANoptosis in Human Peripheral Neutrophils: An Ex Vivo Model. BACKGROUND: Propofol emulsion, a widely used anesthetic in clinical practice, can lead to propofol infusion syndrome (PRIS) when improperly administered. PRIS is characterized by dyslipidemia and cytotoxic damage, particularly affecting peripheral neutrophils. METHODS: Using an ex vivo whole blood model followed by flow cytometric analysis, this study elucidates the mechanisms underlying PRIS-induced cytotoxicity. RESULTS: Significant lipid droplet accumulation and increased neutrophil cell death were observed, with cell granularity correlating strongly with lipid droplet levels. Apoptosis was confirmed via cleaved caspase-3 detection and Western blot analysis, while necroptosis and pyroptosis were associated with increased pRIPK1 and cleaved caspase-1 expressions. A multicolor cytometric method identified elevated PANoptosis, characterized by the combined activation of these pathways. Inhibition of lipid lipase reduced lipolysis and lipid droplet accumulation, highlighting the role of free fatty acid in PANoptosis induction. Reactive oxygen species (ROS), particularly mitochondria-related ROS, were significantly elevated and correlated with lipid droplet levels. Mitochondrial dysfunction, indicated by a loss in mitochondrial transmembrane potential, was mitigated by ROS inhibitors, which also reduced PANoptosis. CONCLUSIONS: The study's findings suggest that free fatty acid and lipid droplet accumulation, in conjunction with oxidative stress, promote overdose propofol emulsion-induced PANoptosis, providing promising therapeutic targets to mitigate cytotoxic effects and offering novel insights into the early detection or therapeutic intervention of immune dysfunction associated with PRIS.