Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy.

Itaconate (ITA) originates by decarboxylation of cis-aconitate catalyzed by the enzyme aconitate decarboxylase 1. It has immunomodulatory properties, but its role in T cells, especially CD4(+) T cells, is mostly unexplored. Here, we examined the effects of ITA and its derivatives 4-octyl itaconate (4-OI) and dimethyl itaconate (DMI) on CD4(+) T cells. We demonstrate that itaconate, 4-OI, and DMI specifically inhibit Th17 cells differentiation under cell-polarizing conditions, reduce IL-17 A secretion and mRNA expression of Th17 cell-related genes including Il17a, Il22 and Il17f. Metabolic profiling, [U-(13)C(5)]-itaconate tracking, and metabolite supplementation studies indicated that Th17 cells uptake ITA through SLC16A1/3 transporters, and exogenous ITA affects amino acid metabolism and oxidative phosphorylation in Th17 cells. Mechanistically, itaconate, 4-OI, and DMI affect mitochondrial quality, reduce mitochondrial membrane potential, lower cellular potential for mitophagy, and mitophagy inducer P62-mediated mitophagy inducer (PMI) can rescue inhibitory effects of itaconate, 4-OI, and DMI on Th17 cells. In vivo, 4-OI treatment suppresses Th17 cells frequency and ameliorates autoimmune disease, imiquimod-induced psoriasis. Our findings reveal itaconate and its derivatives as specific negative regulators of Th17-type response, and ITA-dependent mechanisms as a potential therapy in autoimmune diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02621-1.