Slc1a4, also known as alanine-serine-cysteine transporter 1 (ASCT1), is a gene encoding a Na-dependent neutral amino acid transporter. It is essential for maintaining amino acid balance in the brain and periphery. In the brain, it plays a crucial role in transporting L-and D-isomers of serine. L-serine is involved in protein and sphingolipid synthesis, while D-serine is a co-agonist for normal neurotransmission through N-methyl-D-aspartate receptors. It also plays roles in pathways related to cell cycle, metabolism, and cancer-related processes [1,2]. Genetic models, such as KO mouse models, are valuable for studying its functions.

In KO mouse models, acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain, resulting in microcephaly, decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioural impairments [3]. Silencing Slc1a4 in HCC cells inhibits cell proliferation, migration, cell cycle, and promotes apoptosis, revealing its role in HCC tumorigenesis [2]. In addition, ASCT1-KO mice display lower levels of brain D-serine, along with neurodevelopmental alterations and deficits in motor function, spatial learning, and affective behavior [4].

In conclusion, Slc1a4 is vital for maintaining serine homeostasis, which is crucial for normal brain development and function. Studies using KO mouse models have revealed its significance in neurodevelopmental and neurodegenerative disorders, as well as in HCC. These findings suggest that Slc1a4 could be a potential therapeutic target for these diseases.