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Itaconate, an immunometabolite derived from ACOD1\/IRG1 activity in activated macrophages, has been implicated in the regulation of inflammatory responses, yet its role in interferon \u03b3 (IFN-\u03b3)\u2013driven antigen presentation programs remains incompletely understood. Here, we demonstrate that the itaconate derivative 4-octyl itaconate (4-OI) suppresses IFN-\u03b3\u2013induced antigen presentation programs in bone marrow-derived macrophages. 4-OI reduced surface major histocompatibility complex class II (MHC II) expression and downregulated key components of the antigen presentation machinery, including CIITA, H2-Ab1, and H2-Eb1. Transcriptomic analysis revealed broad suppression of IFN-\u03b3\u2013responsive immune pathways, particularly those associated with antigen processing and inflammatory signaling. Mechanistically, 4-OI attenuated IFN-\u03b3\u2013induced phosphorylation of JAK1, JAK2, and STAT1, and pharmacological inhibition of JAK signaling phenocopied its effects on MHC II expression, implicating involvement of the IFN-\u03b3\u2013JAK\u2013STAT1\u2013CIITA axis. In vivo, 4-OI similarly reduced IFN-\u03b3\u2013induced MHC II expression in splenic macrophages, accompanied by decreased PD-L1 expression as a parallel marker of macrophage activation. Together, these findings identify 4-OI as an immunometabolic regulator of IFN-\u03b3\u2013driven macrophage activation, associated with modulation of the JAK\u2013STAT1\u2013CIITA signaling axis and suppression of antigen presentation programs.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag255","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:03:41Z","timestamp":1791331421000},"source":"Crossref","is-referenced-by-count":0,"title":["4-Octyl itaconate suppresses IFN-\u03b3\u2013induced MHC II expression in bone marrow\u2013derived macrophages"],"prefix":"10.1093","volume":"215","author":[{"given":"Zhiying","family":"Zhou","sequence":"first","affiliation":[{"name":"Affiliated Zhejiang Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang,","place":["China"]},{"name":"Zhejiang University School of Medicine , Hangzhou, 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