Slc6a8, encoding a membrane protein, is a creatine transporter that can transport creatine inside and outside the cell in a Na+ and Cl-- dependent manner [3,4]. It is involved in maintaining cellular creatine levels, which is crucial for energy metabolism as creatine acts as a key source of cellular energy reserve. In the central nervous system, its distribution and function are related to brain creatine metabolism and transport [5].

Genetic studies have shown significant impacts of Slc6a8. Ablation of Slc6a8 in mice altered macrophage-mediated immune responses in vivo, revealing that creatine, taken up by Slc6a8, reprograms macrophage polarization by suppressing M(interferon-γ [IFN-γ]) yet promoting M(interleukin-4 [IL-4]) effector functions [1]. In cancer research, inhibition of the SLC6A8 transporter in mouse models robustly inhibited creatine import, reduced intracellular phosphocreatine and ATP levels, and induced tumor apoptosis, suppressing colon cancer progression [2]. In hepatocellular carcinoma cell lines, SLC6A8 knockdown significantly induced apoptosis and suppressed cell migration and invasion [4].

In conclusion, Slc6a8 is essential for cellular creatine uptake, playing a significant role in macrophage polarization in the immune system and in the progression of various cancers, such as colon and liver cancers. Gene knockout or knockdown models of Slc6a8 have been instrumental in uncovering its functions in these biological processes and disease conditions.