Mfsd2b, a member of the major facilitator superfamily, is the exclusive sphingosine-1-phosphate (S1P) transporter in red blood cells (RBC) and platelets [1,4,5]. S1P is a potent lipid mediator involved in multiple biological processes such as endothelial permeability regulation, vascular development, platelet aggregation, and thrombus formation [1,2,3].

Gene knockout studies have been crucial in revealing Mfsd2b's functions. In Mfsd2b-deficient RBC, large accumulations of S1P and sphingosine occur, coinciding with stomatocytosis and membrane abnormalities, suggesting an impact on RBC deformability [1]. Platelet-specific Mfsd2b knockout mice show impaired platelet morphology and functions, with significantly reduced thrombus formation, indicating Mfsd2b's importance in thrombotic functions [3]. Global deletion of Mfsd2b and Spns2 (another S1P transporter) in mice leads to embryonic lethality beyond E14.5 due to severe hemorrhage and blood vessel integrity defects, while post-natal compound deletion makes mice highly susceptible to anaphylaxis [2]. Additionally, Mfsd2b-deficient mice are protected against hypertension-induced cardiac remodeling as myocardial S1P seems to inhibit L-type-Ca2+ channels through PP2A activation [6].

In conclusion, Mfsd2b plays essential roles in maintaining normal physiological functions related to S1P transport. Its deficiency in KO mouse models has revealed its significance in RBC homeostasis, platelet-mediated thrombosis, vascular development and maintenance, and cardiac function in the context of hypertension-induced remodeling. These findings offer potential insights into treating thrombotic disorders, anaphylaxis, and heart failure [1,2,3,6].