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Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention. • Sphingolipid drives astrocyte pathogenic activities via cPLA2-MAVS-NF-κB • cPLA2 displaces HK2 from MAVS, limiting the metabolic support of neurons by astrocytes • Miglustat suppresses astrocyte cPLA2-MAVS-NF-κB pro-inflammatory signaling • Miglustat is a candidate drug for repurposing to treat secondary progressive MS By exploring the immunometabolic pathways that drive pro-inflammatory astrocyte activities, sphingolipid metabolism is identified as a promising therapeutic target in CNS inflammation. [ABSTRACT FROM AUTHOR]