Small-molecule ACOD1 inhibition attenuates colitis and tumor growth through a shared myeloid mechanism, diverging from genetic deletion
Year: 2026
Type: preprint
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-κB 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.
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223238185