MFSD2A: a molecular nexus linking blood–brain barrier, lipid metabolism, and ischemia–reperfusion injury

Major facilitator superfamily domain-containing protein 2A (MFSD2A) is a central molecular player in maintaining the blood-brain barrier (BBB). It exerts dual protective effects in ischemia-reperfusion injury (IRI): MFSD2A regulates the lipid composition of brain endothelial cell membranes through its sodium-dependent transport of docosahexaenoic acid-conjugated lysophosphatidylcholine (LPC-DHA); this lipid remodeling thereby maintains the characteristic low permeability of the BBB by suppressing caveolae-mediated transcytosis. This review systematically analyzes the tissue distribution patterns of MFSD2A, the protein structural features, and its biological functions both in physiological and pathological conditions. We further reveal its cell type-specific regulatory networks. Notably, acute-phase of IRI induces downregulation of MFSD2A and subsequent BBB leakage. MFSD2A not only serves as a molecular switch to enhance brain-targeted drug delivery (e.g., temporarily inhibiting its activity to improve nanoparticle transport across the BBB) but may also become a therapeutic target for maintaining BBB integrity (e.g., agonist development). This review provides a novel framework for understanding MFSD2A's multidimensional mechanisms in neurological diseases and its potential for clinical translation.