Mesenchymal Stromal Cells in Immunometabolic Regulation: A Review of Itaconate-Mediated Mechanisms

Immunometabolism has emerged as a central regulator of immune responses, linking cellular metabolism to inflammatory signaling and tissue homeostasis. Among tricarboxylic acid (TCA) cycle-derived metabolites, itaconate has gained recognition as an important metabolic feedback regulator promoting inflammatory resolution. Mesenchymal stromal/stem cells (MSCs) are multipotent cells widely recognized for their immunomodulatory and regenerative properties, primarily mediated through paracrine signaling and metabolic adaptation. Increasing evidence indicates that MSC immunoregulatory function is closely associated with metabolic reprogramming involving glycolysis, mitochondrial activity, lipid metabolism, and amino acid pathways. Within this context, itaconate has emerged as a potential metabolic interface linking innate immune activation to MSC function. This narrative review summarizes current evidence supporting both direct and indirect interactions between itaconate signaling and MSC biology. Itaconate and its derivatives influence MSC viability, apoptosis resistance, differentiation potential, and redox balance, while indirectly modulating macrophage polarization and inflammatory microenvironment remodeling through extracellular vesicles and paracrine communication. Despite these advances, critical questions remain regarding endogenous itaconate production by MSCs and its effects on MSC secretome composition and immunoregulatory activity. A deeper understanding of the itaconate-MSC axis may enable metabolic preconditioning strategies aimed at enhancing MSC-based therapies for inflammatory and immune-mediated diseases.