The transforming transforming growth factor-beta (TGF-beta) signaling pathway plays a key role in the fibrotic process in systemic scleroderma (SSc). Curcumin, a Turmeric root extract, has been demonstrated to exert antifibrotic activity. In the present study, we carefully investigated the effect of curcumin on TGF-beta signaling and its potential mechanism in SSc fibroblasts. We demonstrated a potent inhibitory effect of curcumin on TGF-beta signaling. Curcumin counteracted TGF-beta-induced phosphorylation of Smad2 but not Smad3. Further study revealed curcumin induced upregulation of TGF-beta-induced factor (TGIF), a negative regulator of TGF-beta signaling. The TGIF silencing results evidenced the essential role of TGIF in curcumin-mediated TGF-beta/Smad2 suppression. Moreover, our data indicated that the upregulation of TGIF by curcumin might result from decreased ubiquitination of TGIF, which blocks its proteasome-mediated degradation. Collectively, our data provide a novel mechanism of curcumin-mediated suppression of fibrotic process in scleroderma. (C) 2011 Elsevier Inc. All rights reserved.