Spns1, also known as protein spinster homolog1, is a major facilitator superfamily protein. It functions as a proton-dependent lysophospholipid transporter, mediating the salvage of lysosomal phospholipids back to the cytosol. This process is crucial for maintaining normal lysosomal function and is part of the lysosomal nutrient recycling pathway, which is essential for cell survival and proper physiological function [1,2]. Genetic models, such as KO mouse models, have been instrumental in studying its functions.

In KO mouse models, Spns1 deficiency leads to lysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), with pathological consequences on lysosomal function. Global KO in mice causes embryonic lethality between E12.5-E13.5, and in postnatal mice, it affects liver functions and alters the PI3K/AKT signaling pathway due to lysolipid accumulation [1,5]. In zebrafish embryos, Spns1 deficiency exacerbates per-and polyfluoroalkyl substances mediated hepatic toxicity and steatosis [6]. In skeletal muscle of mice, Spns1 ablation drives atrophy by disrupting mitophagy, mitochondrial function, and apoptosis [4]. Conditional knockout of Spns1 in megalin-expressing cells in the kidney leads to endocytic and lysosomal defects, accompanied by iron overload [3]. In zebrafish, the spns1 mutant shows cardiac defects including abnormal endocardial organization and impaired valve formation [7].

In conclusion, Spns1 is essential for lysosomal phospholipid salvage, normal lysosomal function, and various physiological processes. Studies using KO/CKO mouse models and other genetic models have revealed its critical roles in embryonic development, liver function, muscle homeostasis, kidney endocytosis, and cardiac valve morphogenesis. These findings suggest that Spns1 may be a potential target for treating diseases related to lysosomal dysfunction, lipid metabolism disorders, and some developmental abnormalities [1-7].