Aconitate decarboxylase 1 (Acod1), also known as immunoresponsive gene 1 (IRG1), is a mitochondrial enzyme that plays a crucial role in immunometabolism. It is responsible for catalyzing itaconate production, which is involved in various biological processes such as oxidative stress, antigen processing, and macrophage polarization. Immune receptors, adapter proteins, ubiquitin ligases, and transcription factors form complex signal transduction networks to control Acod1 expression in a context-dependent manner [1,2,5].

In cancer, Acod1-deficient macrophages in the induced pluripotent stem cell-derived CAR-macrophage (CAR-iMAC) platform are polarized towards a pro-inflammatory state, enhancing anti-cancer functions like ROS production, phagocytosis, and cytotoxicity in vitro and tumor repression in ovarian or pancreatic cancer mouse models [3]. In arthritis, Acod1-deficient mice show increased osteoclast numbers and bone erosion, while treatment with the itaconate derivative 4-octyl-itaconate alleviates inflammatory bone loss, indicating Acod1 suppresses osteoclast differentiation by inhibiting succinate dehydrogenase-dependent ROS production and Hif1α-mediated aerobic glycolysis [4]. In atherosclerotic mice, transplantation of Acod1 -/- bone marrow leads to a more stable plaque phenotype [6]. In spinal cord injury, transcriptional blockage of Acod1 in microglia exacerbates neuroinflammation and oxidative stress and neurological dysfunction in mice [7]. In breast cancer, Acod1 ablation in tumor-infiltrating neutrophils (TINs) reduces TIN infiltration and metastasis, enhancing antitumor T-cell immunity [8].

In summary, Acod1 is a key regulator in immunometabolism. Studies using gene knockout mouse models have revealed its significant roles in various disease areas such as cancer, arthritis, atherosclerosis, spinal cord injury, and breast cancer metastasis. These models help to understand how Acod1-mediated immunometabolism affects disease-related biological processes, providing potential therapeutic targets for these diseases.

References:

1. Wu, Runliu, Chen, Feng, Wang, Nian, Tang, Daolin, Kang, Rui. 2020. ACOD1 in immunometabolism and disease. In Cellular & molecular immunology, 17, 822-833. doi:10.1038/s41423-020-0489-5. https://pubmed.ncbi.nlm.nih.gov/32601305/

2. Wu, Runliu, Liu, Jiao, Tang, Daolin, Kang, Rui. . The Dual Role of ACOD1 in Inflammation. In Journal of immunology (Baltimore, Md. : 1950), 211, 518-526. doi:10.4049/jimmunol.2300101. https://pubmed.ncbi.nlm.nih.gov/37549395/

3. Wang, Xudong, Su, Siyu, Zhu, Yuqing, Li, Wei, Zhang, Jin. 2023. Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors. In Nature communications, 14, 5778. doi:10.1038/s41467-023-41470-9. https://pubmed.ncbi.nlm.nih.gov/37723178/

4. Kachler, Katerina, Andreev, Darja, Thapa, Shreeya, Schett, Georg, Bozec, Aline. 2024. Acod1-mediated inhibition of aerobic glycolysis suppresses osteoclast differentiation and attenuates bone erosion in arthritis. In Annals of the rheumatic diseases, 83, 1691-1706. doi:10.1136/ard-2023-224774. https://pubmed.ncbi.nlm.nih.gov/38964754/

5. Wu, Runliu, Kang, Rui, Tang, Daolin. 2022. Mitochondrial ACOD1/IRG1 in infection and sterile inflammation. In Journal of intensive medicine, 2, 78-88. doi:10.1016/j.jointm.2022.01.001. https://pubmed.ncbi.nlm.nih.gov/36789185/

6. Harber, Karl J, Neele, Annette E, van Roomen, Cindy Paa, Van den Bossche, Jan, de Winther, Menno Pj. 2024. Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques. In Redox biology, 70, 103054. doi:10.1016/j.redox.2024.103054. https://pubmed.ncbi.nlm.nih.gov/38309122/

7. Qian, Zhanyang, Xia, Mingjie, Zhao, Tianyu, Li, Haijun, Yang, Lei. . ACOD1, rather than itaconate, facilitates p62-mediated activation of Nrf2 in microglia post spinal cord contusion. In Clinical and translational medicine, 14, e1661. doi:10.1002/ctm2.1661. https://pubmed.ncbi.nlm.nih.gov/38644791/

8. Zhao, Yun, Liu, Zhongshun, Liu, Guoqiang, Wan, Jun, Lu, Xin. . Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. In Cell metabolism, 35, 1688-1703.e10. doi:10.1016/j.cmet.2023.09.004. https://pubmed.ncbi.nlm.nih.gov/37793345/