ABHD8 is an α/β-hydrolase domain-containing protein that functions as a negative regulator of NLRP3-driven inflammation. Its primary mechanism involves promoting NLRP3 degradation through chaperone-mediated autophagy (CMA) 1. ABHD8 acts as a molecular scaffold, recruiting the palmitoyltransferase ZDHHC12 to NLRP3 to facilitate NLRP3 palmitoylation, which marks the protein for CMA-mediated degradation and subsequent inflammasome inactivation 1. ABHD8 deficiency stabilizes NLRP3 protein and promotes inflammasome activation, while overexpression ameliorates LPS- and alum-induced NLRP3 activation in vivo 1. Notably, SARS-CoV-2 nucleocapsid protein impairs the ABHD8-NLRP3 interaction, elevating NLRP3 levels and triggering excessive inflammation 1. Beyond inflammasome regulation, ABHD8 exhibits pleiotropic disease associations. Genetic variants at the 19p13.11 locus containing ABHD8 show suggestive significance for aerodigestive squamous cell cancer susceptibility 2, and functional studies confirm that risk alleles increase ABHD8 promoter transactivation in breast and ovarian cancers 3. ABHD8 expression is also associated with mitochondrial lipid metabolism gene signatures in colorectal cancer prognosis 4, DNA methylation patterns in secondary progressive multiple sclerosis outcomes 5, and epithelial ovarian cancer risk through methylation-mediated gene regulation 6. These findings position ABHD8 as a potential therapeutic target for NLRP3 inflammasome-associated diseases.