FASN-Dependent NLRP3 Palmitoylation Drives Inflammasome Activation in Periodontitis [dataset1]

Here we show that FASN expression is elevated in gingival tissues from aged individuals and patients with periodontitis. Using a ligature-induced periodontitis (LIP) model, pharmacological inhibition of FASN with C75 attenuated alveolar bone loss, reduced inflammatory cytokines and cell death in gingival crevicular fluid, and suppressed NLRP3 inflammasome activation in gingival tissues.

Mechanistically, FASN inhibition led to substrate availability for NLRP3 palmitoylation, selectively impairing its interaction with ASC and consequently disrupting inflammasome assembly. Furthermore, enhanced palmitoylated NLRP3 was detected in gingival tissues upon LIP induction, also under obese-prone conditions, suggesting a novel disease-associated modification. Collectively, these findings uncover a previously unrecognized FASN–NLRP3 palmitoylation axis that regulates inflammasome activation in periodontitis and its associated high-risk metabolic states.