The transforming growth factor (TGF)-β/Smad signal transduction pathway is closely associated with hypertrophic scar (HS) formation.Smad interacting protein 1 (SIP1) is a cytoplasmic protein that efficiently regulates Smad2-/3-dependent signaling within the TGF-β 1 pathway.SIP1 influences collagen synthesis in the HS through a heretofore unknown mech-anism.This study investigated the role of the SIP1-mediated TGF-β 1/Smad signaling pathway in extraceilular matrix (ECM) protein production and hypertrophic scarring.Consequently, SIP1 expression was markedly lower in HS vs.normal skin (NS) tissue, and a-smooth muscle actin (a-SMA) content and collagen Ⅰ/Ⅲ (Col Ⅰ/Ⅲ) synthesis were inversely correlated with SIP 1 expression.Furthermore, SIP1 inhibited Smad2/3 phosphorylation in vitro, and improved the collagen-based architecture of the scar while reducing collagen expression and overall scar formation in a rabbit ear model of HS.Based on these findings, we propose that SIP1 acts as a molecular modulator capable of altering Smad2-/3-facilitated signaling through the control of Smad phosphorylation, thus inhibiting a-SMA and collagen upregulation in fibroblasts and, ultimately, HS formation.The low SIP1 content in scar tissue also suggests that SIP1 (and positive regulation thereof) is a prospective target for selective HS drug therapy.