Slc13a3, encoding the plasma membrane Na+ /dicarboxylate cotransporter 3, imports 4-6 carbon dicarboxylates and N-acetylaspartate (NAA) into cells. It is mainly expressed in the kidney, astrocytes, and choroid plexus, playing roles in multiple biological processes. It is involved in pathways related to ferroptosis, immune response, and metabolism, and its malfunction is associated with certain diseases [4,6,7].

In cancer research, genetic ablation of Slc13a3 in tumors or deletion of ACOD1 in macrophages (an enzyme for itaconate synthesis) sensitizes tumors to ferroptosis, curbs tumor progression, and enhances immune checkpoint blockade (ICB) efficacy. This reveals that Slc13a3-mediated itaconate uptake by tumor cells from tumor-associated macrophages activates the NRF2-SLC7A11 pathway, endowing ferroptosis resistance and impairing tumor immunity [1]. In liver cancer, silencing of Slc13a3 depletes glutathione (GSH), induces autophagic ferroptosis in β-catenin-activated liver cancer cells, and both genetic inhibition of Slc13a3 and a small molecule inhibitor suppress β-catenin-driven hepatocarcinogenesis in mice [2]. In hepatic antibacterial innate immunity, liver-specific deletion of Slc13a3 impairs this immunity both in vivo and in vitro, indicating that SLC13A3-mediated itaconate uptake in mouse hepatocytes induces transcription-factor-EB-dependent lysosomal biogenesis and improves antibacterial innate immunity [3]. In mouse models of Canavan leukodystrophy, astroglial conditional Slc13a3 knockout reversed brain NAA elevation and improved motor function [5].

In conclusion, Slc13a3 is crucial in processes like ferroptosis, immune regulation, and metabolism. Gene knockout (KO) and conditional knockout (CKO) mouse models have significantly contributed to understanding its role in cancer, hepatic antibacterial immunity, and Canavan leukodystrophy, providing potential therapeutic targets for these disease areas.

References:

1. Lin, Heng, Tison, Kole, Du, Yuheng, Wang, Shaomeng, Zou, Weiping. 2024. Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance. In Cancer cell, 42, 2032-2044.e6. doi:10.1016/j.ccell.2024.10.010. https://pubmed.ncbi.nlm.nih.gov/39515327/

2. Zhao, Wennan, Wang, Xue, Han, Lifeng, Chen, Xin, Zhang, Youcai. 2024. SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis. In Nature communications, 15, 7522. doi:10.1038/s41467-024-51860-2. https://pubmed.ncbi.nlm.nih.gov/39215042/

3. Chen, Chao, Liu, Caiyun, Sun, Pengkai, Liu, Ping, Li, Xinjian. 2024. Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity. In Developmental cell, 59, 2807-2817.e8. doi:10.1016/j.devcel.2024.07.011. https://pubmed.ncbi.nlm.nih.gov/39116875/

4. Dewulf, Joseph P, Wiame, Elsa, Dorboz, Imen, Nassogne, Marie-Cécile, Schiff, Manuel. 2019. SLC13A3 variants cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation. In Annals of neurology, 85, 385-395. doi:10.1002/ana.25412. https://pubmed.ncbi.nlm.nih.gov/30635937/

5. Hull, Vanessa L, Wang, Yan, McDonough, Jennifer, Guo, Fuzheng, Pleasure, David. 2024. Astroglial conditional Slc13a3 knockout is therapeutic in murine Canavan leukodystrophy. In Annals of clinical and translational neurology, 11, 1059-1062. doi:10.1002/acn3.52010. https://pubmed.ncbi.nlm.nih.gov/38282243/

6. Hussain, Syeda Iqra, Muhammad, Nazif, Shah, Salah Ud Din, Wasif, Naveed, Khan, Saadullah. 2023. Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability. In BMC neurology, 23, 353. doi:10.1186/s12883-023-03397-y. https://pubmed.ncbi.nlm.nih.gov/37794328/

7. Schlosser, Pascal, Scherer, Nora, Grundner-Culemann, Franziska, Li, Yong, Köttgen, Anna. 2023. Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine. In Nature genetics, 55, 995-1008. doi:10.1038/s41588-023-01409-8. https://pubmed.ncbi.nlm.nih.gov/37277652/