Microglial dysfunction contributes to multiple sclerosis (MS) pathogenesis, yet the link between epigenetic regulation and inflammatory cell death (PANoptosis) remains unclear. This study explores NOD-like receptor family CARD domain containing 5 (NLRC5) as a regulator of microglial PANoptosis in MS. Transcriptomic data from experimental autoimmune encephalomyelitis (EAE) microglia (GSE253318) and GEO datasets (GSE78809, GSE154228) were integrated to identify PANoptosis-related genes. Mendelian randomization (MR) linked NLRC5 expression to proteomic targets using UK Biobank and deCODE Iceland protein quantitative trait loci (pQTLs). Methylation quantitative trait locus (mQTL) analysis assessed MS-associated CpG sites. Lipopolysaccharide (LPS)-treated BV2 microglial models were used to validate NLRC5-PANoptosome assembly via Western blot and immunofluorescence. NLRC5 was identified as a hub gene in PANoptosis-related pathways. MR suggested modest associations between NLRC5 expression and apoptotic (GABA Type A Receptor-Associated Protein (GABARAP), BR Serine/Threonine Kinase 2 (BRSK2), TNF Superfamily Member 12 (TNFSF12)) and apoptotic/necroptotic (BCL2) effectors, consistent across inverse-variance weighted (IVW), Bayesian weighted Mendelian randomization (BWMR), and generalized summary-data-based Mendelian randomization (GSMR) methods, though effect sizes were small. Hypermethylation of NLRC5 (cg04097610) showed a potential protective association with MS risk (odds ratio (OR) = 0.885, P = 0.039). In vitro, LPS stimulation upregulated NLRC5, ZBP1, ASC, and caspase-8, supporting PANoptosome activation. NLRC5 may regulate microglial PANoptosis through epigenetic and proteomic mechanisms, linking inflammatory cell death to MS progression. These findings suggest NLRC5 as a candidate regulator and potential therapeutic target, although further validation in human studies is required.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.