FBLN2 (fibulin-2) is a secreted extracellular matrix glycoprotein that functions as a calcium-dependent adapter mediating interactions between fibronectin, fibrillin-1, and elastin. 1 It is essential for basement membrane integrity and microfibril organization in tissues including mammary epithelium and lung vasculature. 2 Mechanistically, FBLN2 exerts context-dependent regulatory functions. In neural tissue, it inhibits oligodendrocyte maturation through Notch pathway engagement, impairing remyelination in demyelinating diseases. 1 In gastric cancer, FBLN2 suppresses proliferation and metastasis via the TGFβ/TGIF2 axis and promotes anoikis (detachment-induced apoptosis), opposing ITGBL1-mediated pro-metastatic signaling. 3 In hepatic disease, FBLN2 marks a highly profibrotic and proinflammatory hepatic stellate cell subpopulation that expands dramatically in alcoholic hepatitis. 4 FBLN2 also associates with myoepithelial differentiation markers in mammary epithelium. 2 Clinically, FBLN2 variants show limited genetic evidence for pulmonary arterial hypertension causality, identified through rare variant analysis in large international cohorts. 5 6 In breast cancer, FBLN2 expression correlates with better prognosis in early-stage disease but worse prognosis in advanced lesions, suggesting stage-dependent prognostic relevance. 2