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

ABSTRACT: Fatty acid synthase (FASN) catalyzes key steps in de novo lipogenesis and has been implicated in inflammatory and metabolic disorders. 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. Therapeutic targeting FASN may thus offer a promising strategy to ameliorate inflammasome-driven inflammation in periodontitis and its complications.

ORGANISM(S): Mus musculus

PROVIDER: GSE306997 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Background: Erectile dysfunction (ED) is a prevalent male sexual disorder, commonly associated with hypertension, though the underlying mechanisms remain poorly understood. Objective: This study aims to explore the role of Fatty acid synthase (Fasn) in hypertension-induced ED and evaluate the therapeutic potential of the Fasn inhibitor C75. Materials and Methods: Erectile function was assessed by determining the intracavernous pressure/ mean arterial pressure (ICP/MAP) ratio, followed by the collection of cavernous tissue for transcriptomic and non-targeted metabolomic analyses. In vitro, a concentration of 10-6 M angiotensin II (Ang II) was applied to rat aortic endothelial cells (RAOECs) to establish a model of hypertension. In vivo, spontaneously hypertensive rats (SHR) were randomly divided into two groups. The SHR+C75 group received intraperitoneal injections of C75 at a dose of 2 mg/kg once a week. After five weeks of treatment, the erectile function of the rats was assessed, and penile tissues were harvested for further analysis. Molecular and protein expression were assessed using Western blotting, qRT-PCR, immunofluorescence staining, and immunohistochemistry. Results: The SHR exhibited ED, indicated by reduced maximum ICP/MAP ratios. Histologically, corpus cavernosum tissue of SHR showed elevated fibrosis and endothelial dysfunction. Additionally, increased expression of the NLRP3 inflammasome, Caspase-1, GSDMD, and the pro-inflammatory cytokines IL-1β and IL-18 was observed. Multi-omics analysis revealed significant enrichment in lipid metabolic pathways, with Fasn identified as a hub gene. In vitro, siFasn and C75 enhanced antioxidant markers Nrf2 and HO-1, reduced ROS accumulation, and suppressed NLRP3 and GSDMD levels. In vivo, C75 treatment restored endothelial function and reversed erectile dysfunction, accompanied by decreased oxidative stress and pyroptosis in the penile corpus cavernosum. Conclusion: These findings suggest that Fasn inhibition may offer a promising therapeutic strategy for hypertension-induced ED by alleviating oxidative stress and suppressing NLRP3 inflammasome-dependent endothelial cell pyroptosis via activation of the Nrf2/HO-1 pathway.

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

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