Mfsd2b, a major facilitator superfamily transporter, is the exclusive sphingosine-1-phosphate (S1P) transporter in red blood cells (RBC) and platelets [1,3,4,5]. S1P is a potent lipid mediator involved in multiple biological processes such as cell growth, survival, and inflammation. MFSD2B-mediated S1P export is crucial for platelet aggregation, thrombus formation, and maintaining plasma S1P levels, which in turn control endothelial permeability and ensure normal vascular development [1].

Gene knockout (KO) mouse models have been instrumental in revealing Mfsd2b's functions. Deletion of Mfsd2b in whole body or platelets impairs platelet morphology and functions, with significantly reduced thrombus formation [3]. Global deletion of Mfsd2b and Spns2 (another S1P transporter) results in embryonic lethality due to severe hemorrhage and blood vessel integrity defects [2]. Postnatal compound deletion makes mice highly susceptible to anaphylaxis, indicating its importance in vascular homeostasis [2]. In RBC, Mfsd2b deficiency leads to S1P and sphingosine accumulation, stomatocytosis, and membrane abnormalities [1,4]. In the heart, Mfsd2b deficiency protects against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel [6].

In conclusion, Mfsd2b plays essential roles in sphingolipid metabolism, platelet function, vascular development and homeostasis, and RBC morphology. KO mouse models have demonstrated its significance in thrombotic disorders, embryonic development, anaphylaxis, and cardiac remodeling, providing valuable insights into potential therapeutic targets for these disease areas.