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

Authors

Papathanassiu, A. E., Li, W., Gilbo, K., Pegg, I. L.

Abstract

Aconitate decarboxylase 1 (ACOD1), the enzyme responsible for synthesis of the immunometabolite itaconate, is widely regarded as an anti-inflammatory brake on tissue damage based on Acod1-deficient mice and itaconate supplementation expermiments. ERG344, a small-molecule ACOD1 inhibitor, suppressed itaconate synthesis in endotoxemic mice and in inflamed colonic mucosa and, contrary to genetic-deletion studies, attenuated acute DSS colitis in an ACOD1-dependent manner. ERG344 treatment was associated with reduced influx of immature monocytes early on and accumulation of mature neutrophils. In syngeneic tumor models, ERG344 prolonged survival and increased tumor-infiltrating lymphocytes and antigen-presenting dendritic cells. Across murine and human colitis scRNA-seq datasets and a ten-model syngeneic tumor atlas, ACOD1 marked interferon-stimulated immature monocytes and maturing neutrophils, and tracked with SOD2 and CD274 independently of interferon and NF-{kappa}B signaling. ACOD1 appears to act through a common myeloid recruitment and maturation mechanism, making pharmacological ACOD1 inhibition a viable therapeutic strategy in colitis and cancer.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Oct 2026.

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