Slc6a8, encoding a membrane protein, is a creatine transporter that moves creatine in and out of cells in a Na+ and Cl--dependent manner [4,6]. Creatine is a key source of cellular energy reserve, and thus Slc6a8 is crucial for maintaining normal cellular energy metabolism. It is also associated with multiple biological processes, and its deficiency can lead to various disorders [1,3,7]. Genetic models, such as knockout (KO) mouse models, are valuable for studying its functions.

Depletion of intracellular creatine by ablation of Slc6a8 in KO mouse models altered macrophage-mediated immune responses in vivo, uncovering a role for creatine in macrophage polarization by modulating responses to cytokines like IFN-γ and IL-4 [1]. In colon cancer, the SLC6A8 inhibitor RGX-202 robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis, suppressing CRC growth across different xenograft models [2]. In females with X-linked creatine transporter deficiency caused by pathogenic variants in SLC6A8, oral supplementation treatment showed potential for clinical improvement [3]. In lung adenocarcinoma, high expression of SLC6A8 was associated with poor survival and its genetic alteration was also related to a poorer prognosis [4]. In non-small cell lung cancer, SLC6A8 overexpression promotes the proliferation, migration and invasion in vitro, accompanied by the activation of notch signaling pathway, while knocking down SLC6A8 can inhibit these effects [5]. In human hepatocellular carcinoma, SLC6A8 knockdown significantly induced apoptosis and suppressed the migration and invasion of Hep3B and Huh-7 cells [6]. In triple-negative breast cancer, SLC6A8-mediated creatine accumulation promoted cell survival and suppressed apoptosis in hypoxic conditions, and was required to facilitate tumor growth in xenograft mouse models [8].

In conclusion, Slc6a8 plays a vital role in multiple biological processes and diseases through its function of transporting creatine. Model-based research, especially KO/CKO mouse models, has revealed its significant contributions to macrophage polarization, cancer progression (such as colon, lung, liver, and breast cancer), and creatine-related deficiency disorders. Understanding Slc6a8 functions provides potential therapeutic targets for these diseases.