SFRP2 is a secreted modulator of Wnt signaling that functions as a key regulator of fibroblast identity and tissue homeostasis. Through direct interaction with Wnt ligands and activation of noncanonical pathways, SFRP2 controls cell growth, differentiation, and epithelial-mesenchymal processes across multiple tissues. In skin, SFRP2 marks a distinct fibroblast population characterized by small, elongated morphology distributed between collagen bundles, with roles in matrix organization and inflammatory cell recruitment 1. During early primate gastrulation, SFRP2 counteracts WNT signaling to sustain pluripotency in the anterior domain 2. SFRP2 dysregulation drives pathogenic fibroblast activation in fibrotic and inflammatory diseases. In idiopathic pulmonary fibrosis, fibroblast-derived sFRP2 activated by TGF-β1 signaling promotes aberrant epithelial differentiation through noncanonical Wnt/calcineurin pathways 3. In psoriasis, SFRP2+ fibroblasts transition to a pro-inflammatory state and amplify immune responses via chemokine production and IL-36G activation 4. Cancer-associated fibroblasts expressing SFRP2 promote tumor progression through enhanced extracellular matrix activity and immune suppression in colorectal cancer 5, 6, while SFRP2 in stromal pericytes suppresses anti-tumor immunity in the abscopal effect 7. Elevated SFRP2 marks profibrotic fibroblast populations in systemic sclerosis correlating with progressive skin fibrosis 8, and uterine fibroblast-derived sFRP2 drives pathological wound healing in uterine scarring 9. In androgenetic alopecia, SFRP2 downregulation permits hair follicle growth 10. Therapeutic approaches targeting SFRP2 or blocking its upstream regulators show promise, including siRNA delivery to prevent uterine scarring and PAI-1 blockade to enhance radioimmunotherapy efficacy.