Fluoxetine promotes IL-10-dependent metabolic defenses to protect from sepsis-induced lethality.

Summary

In preclinical models, fluoxetine protects against sepsis lethality by elevating circulating IL-10, independent of peripheral serotonin, thereby preventing sepsis-induced hypertriglyceridemia and cardiac metabolic dysfunction. The study defines an immunometabolic defense mechanism with repurposing potential for a widely used SSRI.

Key Findings

• Fluoxetine-mediated protection from sepsis is independent of peripheral serotonin signaling.
• Fluoxetine increases circulating IL-10, which is necessary for protection against sepsis-induced hypertriglyceridemia.
• IL-10–dependent effects prevent cardiac glucose oxidation impairment, ectopic lipid accumulation, ventricular stretch, and possible cardiac failure.

Clinical Implications

Do not change practice yet, but the data justify prospective, controlled trials testing fluoxetine as adjunctive therapy in sepsis with IL-10 and cardiometabolic endpoints. Patient selection, dosing, and safety (e.g., QT risk, bleeding) require careful evaluation.

Limitations

• Preclinical study without randomized clinical validation.
• Dosing, timing, and safety profile for sepsis populations were not defined.

Future Directions

Conduct phase 2 randomized trials of fluoxetine as adjunctive therapy in sepsis, stratified by baseline IL-10 levels and cardiometabolic phenotypes; delineate central versus peripheral mechanisms and define optimal dosing windows.