Metabolic-microbial crosstalk drives inflammasome activation: fasn and palmitoylation mediate palmitate-Porphyromonas gingivalis synergy in macrophage-like cells

Periodontitis is a chronic inflammatory disease that is exacerbated by metabolic disorders such as obesity, which is associated with elevated circulating saturated fatty acids and lipotoxic stress. Palmitate, a prominent saturated fatty acid, modulates innate immune responses, while Porphyromonas gingivalis , a key periodontal pathogen, is a potent trigger of inflammation. The NLRP3 inflammasome integrates metabolic and microbial danger signals to promote caspase‑1 activation and the maturation of IL‑1β and IL‑18, yet the interaction between metabolic stress and microbial stimulation remains poorly defined. Using U937 macrophage‑like cells, we investigated how palmitate modulates inflammasome activation and cytokine secretion in response to P. gingivalis and related TLR stimuli. Palmitate alone had limited effects on IL-1β and IL-18 secretion but acted as an enhancer of cytokine release when combined with microbial or TLR stimulation. Inhibition of NLRP3 reduced cytokine secretion but did not prevent palmitate‑induced cytotoxicity, indicating partial inflammasome dependence. Blocking protein palmitoylation partially attenuated IL‑1β potentiation, while inhibition of fatty acid synthase strongly suppressed IL‑1β secretion induced by combined palmitate and P. gingivalis exposure. These findings identify a metabolic-microbial axis that enhances inflammasome‑dependent inflammation and may contribute to heightened periodontal disease severity in individuals with metabolic dysfunction.