MFSD2A in health and disease: lysolipid transport, barrier physiology, and translational boundaries

Abstract Major facilitator superfamily domain-containing protein 2A (MFSD2A) is a sodium-dependent lysolipid transporter that delivers lysophosphatidylcholine-bound fatty acids, particularly docosahexaenoic acid, across specialized cellular interfaces. This Review synthesizes structural, biochemical, physiological, genetic, and disease evidence through an evidence-weighted transport-to-barrier-to-disease framework. We first examine substrate recognition, sodium coupling, conformational transport, and the membrane lipid consequences of lysophosphatidylcholine uptake. We then detail the best-established physiological setting, central nervous system endothelium, where MFSD2A supports brain docosahexaenoic acid accretion, blood–brain barrier maturation, and suppression of caveolae-mediated transcytosis. Evidence from the retina, placenta, lung, kidney, epidermis, and immune cells is compared to define tissue-specific deployment rather than a universal downstream pathway. Rare biallelic variants and experimental loss-of-function models provide the strongest disease evidence, linking impaired lysolipid transport to deficient brain lipid supply, microcephaly, and neurodevelopmental abnormalities. Acquired vascular injury studies associate MFSD2A dysregulation with barrier leakage, whereas proposed roles in cancer, immunotherapy response, and patient stratification remain context-dependent and largely associative. We also assess translational concepts, including barrier stabilization, central nervous system drug delivery, biomarker development, and structure-guided modulation, emphasizing unresolved requirements for selectivity, reversibility, safety, and prospective validation. By distinguishing transporter-intrinsic mechanisms from secondary lipid remodeling and disease correlations, this Review clarifies which functions are established, which are tissue restricted, and which remain hypotheses. This framework identifies experimental priorities for linking MFSD2A activity to clinically informative phenotypes without extrapolating beyond current evidence.