Itaconate drives pro-inflammatory responses through proteasomal degradation of GLO1.

Itaconate is a small-molecule metabolite generated by the enzyme aconitate decarboxylase 1 (ACOD1), which is upregulated during inflammation. Traditionally, itaconate has been recognized for its anti-inflammatory properties; however, this study reveals a pro-inflammatory mechanism of itaconate in macrophages. We demonstrate that itaconate promotes the proteasomal degradation of glyoxalase 1 (GLO1) via Cys139. GLO1 is crucial for detoxifying methylglyoxal (MGO), a glycolysis byproduct that leads to advanced glycation end-products (AGEs). Elevated concentrations of itaconate correlate with reduced GLO1 expression in peripheral blood mononuclear cells (PBMCs) from patients with sepsis, linking increased itaconate concentrations to heightened MGO and AGE production. Functionally, itaconate-induced degradation of GLO1 promotes the accumulation of MGO and AGEs, thereby exacerbating inflammatory responses. In vivo, itaconate-treated myeloid-specific Ager conditional knockout mice exhibited reduced inflammation and improved survival in experimental sepsis models compared to wild-type controls. Collectively, these findings reveal a novel function of itaconate in immunometabolism, shedding light on its complex involvement in lethal infections.