Upon liver injury, quiescent hepatic stellate cells (HSC), the most relevant cell type for hepatic fibrogenesis, become active and over-produce extracellular matrix (ECM). Connective tissue growth factor (CTGF) promotes ECM production. Over-expression of CTGF during hepatic fibrogenesis is induced by transforming growth factor-beta (TGF-). We recently demonstrated that curcumin reduced cell growth and inhibited ECM gene expression in activated HSC. Curcumin induced gene expression of the peroxisome proliferator-activated receptors-gamma (PPAR) and stimulated its activity in activated HSC, which was required for curcumin to suppress ECM gene expression, including I(I) collagen. The underlying mechanisms remain largely unknown. The aim of this study is to elucidate the mechanisms by which curcumin suppresses I(I) collagen gene expression in activated HSC. We hypothesize that inhibition of I(I) collagen gene expression in HSC by curcumin is mediated by suppressing CTGF gene expression through attenuating oxidative stress and interrupting TGF- signaling. The present report demonstrates that curcumin significantly reduces the abundance of CTGF in passaged HSC and suppresses its gene expression. Exogenous CTGF dose-dependently abrogates the inhibitory effect of curcumin. Activation of PPAR by curcumin results in interruption of TGF- signaling by suppressing gene expression of TGF- receptors, leading to inhibition of CTGF gene expression. The phyto-chemical shows its potent antioxidant property by significantly increasing the level of total glutathion (GSH) and the ratio of GSH/GSSG in activated HSC. de novo synthesis of cellular GSH is a prerequisite for curcumin to interrupt TGF- signaling and to inhibit gene expression of CTGF and I(I) collagen in activated HSC. Taken together, our results demonstrate that inhibition of I(I) collagen gene expression by curcumin in activated HSC results from suppression of CTGF gene expression through increasing cellular GSH contents and interrupting TGF- signaling. These results provide novel insights into mechanisms underlying inhibition of HSC activation by curcumin.