Activation of pancreatic stellate cells (PSCs) is the key process in the development of pancreatic fibrosis, a common feature of chronic pancreatitis and pancreatic cancer. In recent studies, curcumin has been shown to inhibit PSC proliferation via an extracellular signal-regulated kinase (ERK)1/2-dependent mechanism. In addition, curcumin is a potent inducer of the cytoprotective enzyme heme oxygenase-1 (HO-1) in other cell types. Therefore, the aims of this study were to 1) characterize the effect of curcumin on HO-1 gene expression in PSCs, 2) explore whether HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation, and 3) clarify the involvement of the mitogen-activated protein kinase (MAPK) family in this context. Cultured rat PSCs were incubated with curcumin and assessed for HO-1 up-regulation by Northern blot analysis, immunoblotting, and activity assays. The effect of HO-1 on platelet-derived growth factor (PDGF)-induced PSC proliferation and MAPK activation was determined by immunoblotting, cell proliferation assays, and cell count analyses. Curcumin induced HO-1 gene expression in PSCs in a timeand dose-dependent manner and inhibited PDGF-mediated ERK1/2 phosphorylation and PSC proliferation. These effects were blocked by treatment of PSCs with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA. Our data provide evidence that HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation. Therefore, therapeutic up-regulation of HO-1 could represent a mode for inhibition of PSC proliferation and thus may provide a novel strategy in the prevention of pancreatic fibrosis.Pancreatic fibrosis is a common histopathological feature in chronic pancreatitis and pancreatic cancer. It is now generally accepted that pancreatic stellate cells (PSCs) play a crucial role in the fibrogenic process (Omary et al., 2007). In response to profibrogenic stimuli, PSCs undergo transdifferentiation from quiescent phenotypes into highly proliferative myofibroblast-like cells, which express the cytoskeletal protein ␣-smooth muscle actin and synthesize increased amounts of extracellular matrix components (Apte et al., 1998;Bachem et al., 1998). Recent studies have identified platelet-derived growth factor (PDGF)-BB as the most potent mitogen for pancreatic stellate cells in culture, and its effects have been extensively studied (Apte et al., 1998;Luttenberger et al., 2000). PDGF stimulates PSC cell proliferation by activating key effectors, including ras, raf, and the extracellular signal-regulated kinase (ERK)1/2 cascade (Jaster et al., 2002;Masamune et al., 2003a). Data from recent studies suggest that p38 mitogenactivated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase (JNK) signaling pathways might also play a role in PSC proliferation ((Masamune et al., 2003b((Masamune et al., , 2004. Thus, modulation of MAPK activation is considered a potential strategy to inhibit PSC growth.Heme oxygenases (HOs) are the rate-limiting enzymes...