{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ACOD1 – also known as immune‐responsive gene 1 (IRG1) – encodes a mitochondria‐localized enzyme that is highly up‐regulated in myeloid cells in response to inflammatory and microbial signals. Upon activation by agents such as lipopolysaccharide, type I interferons, or even steroid hormones, ACOD1 catalyzes the conversion of the tricarboxylic acid cycle intermediate cis‐aconitate into itaconate, a metabolite that plays a central role in reprogramming macrophage metabolism and regulating inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Itaconate acts as an anti‐inflammatory mediator by directly modifying key proteins – for example, through alkylation of cysteine residues on KEAP1 – thus promoting activation of the transcription factor Nrf2 and consequent expression of antioxidant and anti‐inflammatory genes. In doing so, the ACOD1/itaconate pathway limits excessive cytokine production and modulates reactive oxygen species levels, which are critical for both the resolution of inflammation and for establishing negative feedback loops that temper type I interferon responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its canonical role in macrophage activation, ACOD1/itaconate has been implicated in tissue protection in various pathological settings. For instance, deletion of ACOD1 exacerbates liver injury by impairing the Nrf2-mediated antioxidative response"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while its induction can limit vascular inflammation associated with abdominal aortic aneurysm formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, ACOD1 expression is modulated during processes as diverse as embryo implantation in the uterus"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "and respiratory syncytial virus infection where it contributes to reactive oxygen species production and lung injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In antimicrobial defense, the ACOD1/itaconate axis is activated by interferon‐regulated transcription factors (such as IRF1), thereby strengthening macrophage bacteriostatic functions and promoting phagosomal delivery of itaconate to limit intracellular pathogens."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, these findings illustrate that ACOD1 functions as a critical metabolic checkpoint linking innate immune activation with the regulation of inflammation, oxidative stress, and tissue protection.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Evanna L Mills, Dylan G Ryan, Hiran A Prag, et al. 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