Cannabidiol selectively attenuates lipotoxic immunometabolic inflammation in human macrophages

The role of saturated fatty acid-induced immunometabolic stress in macrophage dysfunction during metabolic disease remains incompletely understood, particularly the interplay between inflammatory signaling and intracellular lipid handling. We employed a tightly controlled palmitic acid (PA)-based lipotoxicity model in PMA-differentiated U937-derived human macrophage-like cells to investigate how lipid excess reshapes inflammatory responses and to evaluate the modulatory effects of cannabidiol (CBD). PA exposure induced a metabolically stressed yet viable macrophage phenotype, characterized by a broad cytokine remodeling profile. This included induction of classical proinflammatory cytokines such as interleukin (IL)-6, together with activation of inflammasome-associated cytokines IL-1β and IL-18 and additional immunoregulatory mediators, while tumor necrosis factor alpha (TNF-α) contributed to the overall inflammatory profile in a multivariate analysis. These changes were accompanied by a significant, time-dependent storage of intracellular triglycerides (TG) consistent with lipid overload and altered lipid handling. CBD co-treatment did not compromise cell viability but selectively attenuated PA-induced inflammatory response in a cytokine-dependent manner, with the most significant reduction observed at higher concentrations. In parallel, CBD significantly reduced intracellular TG accumulation under lipotoxic conditions. Collectively, these findings define a lipotoxicity-associated macrophage phenotype driven by saturated fatty acids and identify CBD as a context-dependent modulator of immunometabolic inflammation. This work provides a controlled experimental framework to study lipid-driven inflammatory dysfunction and supports the potential of CBD as a targeted strategy to modulate metabolic inflammation without broadly suppressing immune function.