Slc17a5, which encodes the lysosomal transmembrane protein sialin, is crucial for the transport of free sialic acid out of the lysosome. Dysfunction of sialin due to pathogenic variations in Slc17a5 leads to free sialic acid storage disorders (FSASDs), causing cellular dysfunction and neurological impairment [1,4,5]. Sialin also functions as an electrogenic 2NO₃⁻/H⁺ cotransporter in the plasma membrane of salivary gland acinar cells, mediating nitrate influx into salivary gland and other cell types, thus contributing to serum nitrate clearance, nitrate recycling, and nitrite-NO homeostasis [2].

In a study targeting the founder variant SLC17A5 c.115C>T (p.Arg39Cys) in human dermal fibroblasts, adenine base editing (ABE) demonstrated significant correction of the pathogenic variant and reduction of free sialic acid, ameliorating disease pathology. The translation of this ABE strategy to mouse embryonic fibroblasts harboring the Slc17a5 c.115C>T variant in homozygosity recapitulated these results, indicating the feasibility of base editing as a therapeutic approach for the FSASD variant SLC17A5 c.115C>T [1]. In another study, dietary nitrate supplementation increased the expression of Sialin (encoded by Slc17a5) in colon epithelial cells, and epithelial cell-conditional Slc17a5-knockout mutant mice showed decreased functional proteins expression of the colon epithelial barrier and reduced proliferation of intestinal epithelial cells, suggesting that Slc17a5 is involved in maintaining colonic homeostasis [3].

In conclusion, Slc17a5 is essential for free sialic acid transport from lysosomes and nitrate transport in certain cells. Mouse models, such as those with the Slc17a5 c.115C>T variant or epithelial cell-conditional Slc17a5-knockout, have been instrumental in revealing its role in FSASDs and colonic homeostasis, providing insights for potential therapeutic strategies for related diseases [1,3].