Drugging trained immunity: immunometabolic and epigenetic control of maladaptive inflammatory memory in chronic...

Chronic inflammatory diseases are usually treated as persistent activation states, yet many disorders also contain a memory component: innate immune cells and their bone marrow progenitors can retain durable metabolic and epigenetic programs after infection, sterile injury, modified lipoproteins, crystals, diet or vaccination. This process, known as trained immunity, improves host defense when appropriately induced but may also amplify maladaptive inflammation in atherosclerosis, gout, rheumatoid arthritis, inflammatory bowel disease, neuroinflammation, chronic pain and metabolic disease. The pharmacological importance of trained immunity is increasing because its core mechanisms are druggable: glycolysis, mTOR-HIF-1 alpha signaling, the mevalonate pathway, tricarboxylic-acid-cycle metabolites, histone methylation and acetylation, chromatin accessibility, NLRP3 inflammasome activity and IL-1 beta signaling. This review critically synthesizes trained immunity as a disease-relevant inflammatory memory program and evaluates repurposed and emerging interventions, including colchicine, IL-1 blockers, statins, metformin, mTOR inhibitors, fumarate/itaconate-related metabolic modulators, BET/HDAC-directed epigenetic strategies and NLRP3 inhibitors. We propose a translational framework in which patients are stratified by inflammatory-memory phenotypes, interventions are matched to dominant metabolic-epigenetic modules, and treatment success is judged by durable resolution without excessive immunosuppression. This approach can help convert trained immunity from a descriptive immunological concept into a practical target class for inflammation pharmacology.