Prophylactic and therapeutic itaconate treatment alleviates COVID-19-associated lung injury

Although itaconate demonstrates anti-inflammatory and antimicrobial properties as an immunomodulatory metabolite, the therapeutic potential and mechanistic basis of vaccine-induced or prophylactic itaconate administration in COVID-19 intervention remains underexplored. Our studies reveal that intranasal delivery of dNS1-RBD significantly upregulates endogenous itaconate production. Subsequent research reals that both systemic (intraperitoneal) and pulmonary-targeted (intranasal) itaconate administration mitigate acute lung injury by augmenting efferocytosis and reprogramming macrophage lipid metabolism. Metabolomic analyses further uncover that exogenous itaconate modulates amino acid flux, with parallel protection observed through ornithine/arginine supplementation, suggesting a universal metabolic preconditioning mechanism. This conserved tolerance pathway, validated in human BALF scRNA-seq datasets, establishes metabolic intervention as a strategic approach to harmonize antiviral responses and inflammation control during viral challenge.