ACOD1 inhibitor ERG344 eases mouse colitis and slows tumors, contrasting with knockout findings
- ERG344 inhibits ACOD1, the enzyme making itaconate, and lowered itaconate in endotoxemic mice and inflamed colon tissue.
- Unlike Acod1-knockout results, the compound reduced acute DSS colitis, and this effect required ACOD1; early immature monocyte influx fell while mature neutrophils accumulated.
- In syngeneic tumor models, treatment extended survival and raised tumor-infiltrating lymphocytes and dendritic cells.
- Single-cell datasets linked ACOD1 to interferon-stimulated immature monocytes and maturing neutrophils, suggesting a shared myeloid recruitment and maturation role.
💡 Points
Drug and knockout disagreeing is the result I'd chase first: acute inhibition can differ from lifelong deletion through developmental compensation, so target validity now rests on the pharmacology. The ACOD1-dependence control helps rule out off-target effects, but I'd still want exposure at the efficacious dose and tissue itaconate levels tied to the effect before taking it further.