Although autoimmunity driven by dendritic cells (DCs) and CD8+ T cells plays a central role in the destruction of melanocytes during vitiligo, effective treatments are scarce due to the lack of approaches that simultaneously address both cell populations. We investigated the link between the immunoregulatory metabolite itaconate and vitiligo progression by measuring serum itaconate concentrations in patients with vitiligo and tracking depigmentation in Acod1 knockout (KO) mice, which lack endogenous itaconate production. We then tested the therapeutic potential of the itaconate derivative dimethyl itaconate (DI) in mouse models of the disease and examined its impact on the recruitment and functional activity of cutaneous DCs and CD8+ T cells both in vivo and ex vivo. Gene expression profiles and involved signaling pathways were also analyzed in DI-exposed CD8+ T cells. Patients with vitiligo displayed increased levels of circulating itaconate. In contrast, itaconate deficiency in Acod1 KO mice led to faster depigmentation following disease induction. Treatment with DI effectively prevented vitiligo progression and supported repigmentation, accompanied by higher systemic itaconate, greater melanocyte numbers, and lower densities of skin-infiltrating CD8+ T cells. At the cellular level, DI suppressed CD8+ T cell activation (CD69), effector cytokine production (IFN-γ), cytotoxic capacity (Gzmb), proliferation, and expression of proinflammatory genes (Csf1, Ifitm1, CD49a, NKG2D, and NKG2A), at least in part through inhibition of the JAK–STAT signaling pathway. Additionally, DI reduced the infiltration of DCs into the skin and decreased the proportion of DCs exhibiting mature and migratory characteristics. These results highlight DI as a small-molecule derivative of an endogenous metabolite that safeguards against autoimmune damage by simultaneously modulating DC and CD8+ T cell responses. This dual-targeting mechanism offers a compelling therapeutic avenue for vitiligo and potentially other organ-specific autoimmune conditions.
