Mfsd2a, a member of the major facilitator superfamily, is a sodium-dependent lysophosphatidylcholine (LPC) transporter. It is crucial for normal brain growth and function as it is the major transporter for the essential omega-3 fatty acid docosahexaenoic acid (DHA) uptake into the brain. Mfsd2a is expressed in the endothelium of the blood-brain barrier micro-vessels and plays a role in maintaining the integrity of the blood-brain barrier, which is essential for providing a proper environment for neural function [1,4].

In Mfsd2a-knockout mice, there is a marked reduction in brain DHA levels, accompanied by neuronal cell loss in the hippocampus and cerebellum, cognitive deficits, severe anxiety, and microcephaly [1]. These mice also have a leaky blood-brain barrier from embryonic stages to adulthood due to increased CNS-endothelial-cell vesicular transcytosis, despite normal vascular network patterning [4]. In the context of acute kidney injury, Mfsd2a haploinsufficient mice show delayed renal function recovery, and treatment with LPC-DHA can improve the situation [5]. In gastric cancer, higher MFSD2A expression in tumor tissues is associated with a better response to anti-PD-1 immunotherapy, and its overexpression in GC cells enhances the efficacy of anti-PD-1 immunotherapy by reprogramming the tumor microenvironment [2]. In glioma, inhibiting Wnt signaling increases temozolomide (TMZ) delivery by downregulating Mfsd2a and enhancing vascular transcytosis [3].

In conclusion, Mfsd2a is essential for the transport of DHA into the brain and for maintaining the integrity of the blood-brain barrier. Its deficiency in mouse models reveals its significance in brain development, cognitive function, and in diseases such as acute kidney injury, gastric cancer, and glioma. These model-based studies help us understand the role of Mfsd2a in biological processes and disease conditions, providing potential targets for therapeutic intervention.