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AIMS The present study aimed to explore the effect of syndecan-1 on keloid fibroblasts. MAIN METHODS Immunohistochemistry and Western blot were employed to assess the expression of syndecan-1. Primary cultured keloid fibroblasts were transfected with syndecan-1 siRNA. The function of syndecan-1 on the proliferation of keloid fibroblasts was investigated through Cell Counting Kit-8 (CCK-8) and flow cytometry. Extracellular matrix, TGF-β1/Smad, and MAPK related proteins were evaluated by Western blot. KEY FINDINGS Syndecan-1 was significantly overexpressed in both keloid tissues and fibroblasts. Moreover, the knockdown of syndecan-1 remarkably attenuated the proliferation of keloid fibroblasts and reduced the content of the extracellular matrix. Importantly, syndecan-1 regulates the expression of the extracellular matrix in keloid fibroblasts via TGF-β1/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. SIGNIFICANCE The current results revealed a crucial function for syndecan-1 in regulating the expression of extracellular matrix and cell proliferation, thereby designating syndecan-1 as a novel target for keloid.