Acod1, also known as Immunoresponsive Gene 1 (IRG1), is a mitochondrial enzyme. It plays a crucial role in immunometabolism, catalyzing itaconate production. Multiple immune-related signal transduction networks, involving immune receptors (e.g., TLRs), adapter proteins (e.g., MYD88), and transcription factors (e.g., NF-κB), control its context-dependent expression [1,2,5]. ACOD1 is important in immunity, as its activation can limit pathogen infection, and it also has implications in embryo implantation [1]. However, abnormal expression can lead to various diseases like tumor progression, neurodegenerative diseases, and immune paralysis [1]. Genetic models, such as gene knockout mouse models, are valuable for studying its functions.

In cancer research, ACOD1-depleted human induced pluripotent stem cell-derived CAR-macrophages exhibit enhanced anti-tumor functions. ACOD1 knockout in these cells leads to a persistent pro-inflammatory state, with increased ROS production, phagocytosis, and cytotoxicity against cancer cells in vitro and in ovarian or pancreatic cancer mouse models [3]. In arthritis, Acod1-deficient mice show increased osteoclast numbers and bone erosion in experimental arthritis, indicating that Acod1 suppresses osteoclast differentiation and bone loss in inflammatory arthritis by inhibiting succinate dehydrogenase-dependent ROS production and Hif1α-mediated aerobic glycolysis [4]. In atherosclerotic plaque studies, Ldlr-/-atherogenic mice transplanted with Acod1-/-bone marrow display a more stable plaque phenotype, suggesting that targeting the ACOD1-itaconate axis could be a potential therapeutic approach for atherosclerosis [6]. In breast cancer, Acod1 ablation in tumor-infiltrating neutrophils (TINs) reduces TIN infiltration, constrains metastasis, and enhances antitumor T-cell immunity, as Acod1 in TINs mediates Nrf2-dependent defense against ferroptosis [7].

In conclusion, Acod1 is a key regulator in immunometabolism. Gene knockout mouse models have revealed its roles in multiple disease areas, including cancer, arthritis, and atherosclerosis. These findings suggest that understanding Acod1 functions can potentially lead to the development of novel therapeutic strategies 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. 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/