MFSD2A in Type 2 Diabetes and Its Complications

Type 2 diabetes mellitus (T2DM) and its vascular complications remain a leading cause of morbidity and mortality worldwide. Endothelial dysfunction is a common pathological denominator underlying diabetic microvascular and macrovascular disease. Major facilitator superfamily domain-containing protein 2A (MFSD2A) is a lysophosphatidylcholine transporter essential for blood–brain barrier integrity that also functions in the retina, liver, placenta, and kidney, participating in lipid homeostasis, inflammation resolution, and barrier maintenance. Emerging evidence links MFSD2A to diabetic complications. Its expression is reduced in the retina and kidney yet upregulated in the fatty liver, while its role in the vascular endothelium under diabetic conditions remains unexplored. In parallel, ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is implicated in diabetic vascular disease. This hypothesis-oriented narrative review examines MFSD2A structure, transport mechanisms, and tissue-specific functions, synthesises current evidence linking MFSD2A to diabetic complications, critically evaluates whether MFSD2A-mediated lipid transport modulates endothelial ferroptosis sensitivity, and identifies key knowledge gaps and therapeutic opportunities. This review identifies that MFSD2A is dysregulated in a tissue-specific pattern in diabetes and finds that the interplay between MFSD2A-mediated DHA transport and endothelial ferroptosis sensitivity represents a critical knowledge gap that is tractable through the tissue-specific, conditionally testable framework developed in this review.