Secreted frizzled-related protein 2 as a context-dependent extracellular signaling hub in development, tissue remodeling, and disease

Abstract

sFRP2, a member of the secreted frizzled-related protein family, is an extracellular protein characterized by a cysteine-rich domain and a netrin-like (NTR) domain. By modulating ligand availability, receptor selection, and microenvironmental signal integration, sFRP2 exerts highly context-dependent biological effects. Accumulating evidence suggests that sFRP2 should no longer be viewed merely as a WNT antagonist, but rather as an extracellular regulatory molecule that links development, tissue repair, and pathological remodeling. This review summarizes the molecular structure, expression patterns, and functional duality of sFRP2, with particular emphasis on its roles in regulating canonical and non-canonical WNT signaling, coordinating receptor bias and receptor switching, and participating in TGF-β-driven fibrosis, CXADR/NO-mediated WNT-independent growth control, endoplasmic reticulum stress-associated repair, and metabolic inflammation. We further discuss its functions within the tumor microenvironment, including the modulation of angiogenesis, cancer-associated fibroblasts, immunosuppression, and tumor cell survival. By integrating receptor bias and receptor switching with WNT-independent signaling, this review extends beyond a predominantly WNT-centered view of sFRP2 and proposes a context-stratified framework for biomarker interpretation and therapeutic targeting based on cellular origin, dominant signaling axis, disease stage, and tissue compartment.