Authors: Lin M-C et al.
Anesthesiology, February 12, 2026.
Overdose propofol emulsion induces PANoptosis in human peripheral neutrophils in an ex vivo model.
This experimental study investigated the cellular mechanisms underlying propofol infusion syndrome (PRIS), focusing on how high doses of propofol emulsion affect human neutrophils. Propofol is widely used for anesthesia and sedation, but prolonged or excessive dosing can lead to PRIS, a rare but potentially fatal complication characterized by metabolic abnormalities, lipid disturbances, cardiac dysfunction, and cellular injury.
Previous research has suggested that lipid metabolism abnormalities and immune cell dysfunction may contribute to PRIS. In this study, the investigators explored whether propofol overdose induces PANoptosis in neutrophils. PANoptosis is a recently described inflammatory cell death pathway that integrates features of apoptosis, necroptosis, and pyroptosis.
The researchers used an ex vivo human whole-blood model combined with flow cytometry and molecular analyses to evaluate neutrophil responses to high concentrations of propofol emulsion. The experiments focused on lipid metabolism changes, oxidative stress, mitochondrial dysfunction, and activation of multiple cell death pathways.
Exposure to high-dose propofol emulsion resulted in significant accumulation of lipid droplets within neutrophils. Increased intracellular lipid content was strongly associated with increased cell granularity and higher rates of neutrophil death.
Markers of several distinct cell death pathways were identified:
• Apoptosis was confirmed through detection of cleaved caspase-3.
• Necroptosis was associated with increased phosphorylated RIPK1 (pRIPK1).
• Pyroptosis was indicated by elevated cleaved caspase-1.
Using a multicolor cytometric analysis, the investigators demonstrated simultaneous activation of these pathways, consistent with PANoptosis.
Further analysis suggested that free fatty acids generated from propofol-associated lipid metabolism played a central role in this process. When lipase activity was inhibited, lipolysis and lipid droplet accumulation decreased, and neutrophil death was reduced. This finding indicates that excessive lipid metabolism contributes to cellular injury.
The study also found strong evidence of oxidative stress. Reactive oxygen species (ROS), particularly those originating from mitochondria, were markedly elevated in neutrophils exposed to high concentrations of propofol emulsion. ROS levels closely correlated with lipid droplet accumulation.
Mitochondrial dysfunction was observed as well, demonstrated by loss of mitochondrial membrane potential. Importantly, treatment with ROS inhibitors reduced mitochondrial injury and significantly decreased the degree of PANoptosis.
These findings suggest a mechanistic pathway in which excessive propofol emulsion leads to increased lipid metabolism and free fatty acid production. This metabolic disturbance generates oxidative stress and mitochondrial dysfunction, ultimately triggering inflammatory cell death through PANoptosis.
The authors propose that targeting lipid metabolism, oxidative stress, or mitochondrial injury may represent potential therapeutic strategies for preventing or mitigating PRIS. In addition, early detection of immune cell dysfunction could potentially serve as a biomarker for impending PRIS in critically ill patients receiving high-dose or prolonged propofol infusions.
Key Points
• Propofol infusion syndrome is a rare but serious complication associated with high-dose or prolonged propofol administration.
• This study used an ex vivo human blood model to examine propofol’s effects on neutrophils.
• High-dose propofol emulsion caused lipid droplet accumulation and increased neutrophil death.
• Multiple cell death pathways were activated simultaneously, consistent with PANoptosis.
• Free fatty acids and oxidative stress played key roles in triggering this inflammatory cell death process.
• Reactive oxygen species inhibitors reduced mitochondrial dysfunction and decreased PANoptosis.
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