Small-molecule ACOD1 inhibition attenuates colitis and tumor growth through a shared myeloid mechanism, diverging from genetic deletion

Aconitate decarboxylase 1 (ACOD1) is an enzyme crucial for producing immunometabolite itaconate, which has been linked to anti-inflammatory actions in tissue damage. Research on ACOD1-deficient mice and itaconate supplementation in experiments has demonstrated its role as a brake on tissue inflammation. However, the small-molecule inhibitor ERG344, which suppresses itaconate synthesis, has shown surprising effects.

In endotoxemic mice and inflamed colonic mucosa, ERG344 treatment, contrary to genetic-deletion studies, attenuated acute DSS colitis in an ACOD1-dependent manner. The inhibitor's action was associated with a reduced influx of immature monocytes early on and an accumulation of mature neutrophils. In syngeneic tumor models, ERG344 treatment prolonged survival and increased tumor-infiltrating lymphocytes and antigen-presenting dendritic cells.

Through an extensive analysis of murine and human colitis scRNA-seq datasets, as well as a ten-model syngeneic tumor atlas, ACOD1 was found to mark interferon-stimulated immature monocytes and maturing neutrophils, and tracked independently of interferon and NF-{kappa}B signaling. It appears that ACOD1 acts through a common myeloid recruitment and maturation mechanism, suggesting that pharmacological ACOD1 inhibition could be a viable therapeutic strategy for both colitis and cancer.