Slc13a3, encoding the plasma membrane Na+/dicarboxylate cotransporter 3 (NaDC3), is mainly expressed in the kidney, astrocytes, and choroid plexus. It imports 4-6 carbon dicarboxylates and N-acetylaspartate (NAA) into the cell, playing important roles in multiple biological processes and associated with various pathways [5,7].

In cancer research, gene-targeted mouse models have provided valuable insights. In liver cancer, activation of β-catenin up-regulates Slc13a3, and its silencing in β-catenin-activated liver cancer cells leads to leucine depletion, mTOR inactivation, GSH depletion, and autophagic ferroptosis. Both genetic inhibition of Slc13a3 and a small molecule inhibitor suppress β-catenin-driven hepatocarcinogenesis in mice, suggesting it as a therapeutic target for liver cancers with GOF CTNNB1 mutations [2].

In the tumor microenvironment, deletion of Slc13a3 in tumors or treatment with its inhibitor sensitizes tumors to ferroptosis, curbs tumor progression, and enhances immune checkpoint blockade (ICB) effectiveness as tumor cells uptake itaconate via Slc13a3 from tumor-associated macrophages (TAMs), activating the NRF2-SLC7A11 pathway to escape immune-mediated ferroptosis [1]. Also, Slc13a3 inhibition enhances the efficacy of anti-CTLA-4 immunotherapy in syngeneic mouse tumor models as itaconate transported by Slc13a3 alkylates PD-L1, stabilizing it and promoting tumor immune evasion [4].

In hepatic antibacterial innate immunity, liver-specific deletion of Slc13a3 impairs this immunity both in vivo and in vitro. Itaconate uptake via Slc13a3 induces TFEB-dependent lysosomal biogenesis to improve antibacterial innate immunity in mouse hepatocytes [3].

In Canavan leukodystrophy murine models, astroglial conditional Slc13a3 knockout reversed brain NAA elevation and improved motor function [6].

In conclusion, Slc13a3 is crucial for the transport of specific molecules and is involved in multiple biological processes. Studies using gene knockout or conditional knockout mouse models have revealed its significance in diseases such as cancer, hepatic antibacterial immunity, and Canavan leukodystrophy. These findings provide potential therapeutic targets and new insights into the pathogenesis of these diseases.