4-Octyl itaconate promotes dendritic cell tolerogenic properties via suppressing STING signaling to delay lupus onset

Abstract Systemic lupus erythematosus (SLE) is a refractory autoimmune disease characterized by immune tolerance breakdown and dendritic cell (DCs) hyperactivation. Tolerogenic DCs (tolDCs) represent a promising therapeutic strategy, yet the regulatory mechanisms remain poorly understood. Here, we investigated the therapeutic potential and mechanism of the 4-octyl itaconate (4OI) and 4OI-induced tolDCs in SLE. In a chromatin-induced murine lupus model, 4OI administration significantly delayed disease onset, reduced proteinuria, anti-dsDNA autoantibodies, and renal pathological injury. Mechanistically, 4OI directly promoted a tolDCs phenotype both in vivo and in vitro, as evidenced by downregulated CD80/CD86, upregulated PD-L1, increased IL-10/TGF-β, and impaired CD4⁺ T cell proliferation. Adoptive transfer of 4OI-induced tolDCs alleviated lupus progression, reducing Tfh, Th1, Th17, and plasma cells while increasing Tregs. Further investigation showed that 4OI promotes tolDCs differentiation by inhibiting STING transcription and phosphorylation. Notably, combining 4OI with the JAK inhibitor produced synergistic therapeutic effects superior to either monotherapy. These findings identify a previously unrecognized role of itaconate derivatives in promoting tolDCs via STING inhibition and suggest that 4OI and 4OI-induced tolDCs represents an attractive candidate for SLE therapy.