The endocannabinoid system (CS) has been implicated in the development of hepatic fibrosis such as schistosomiasis-associated liver fibrosis (SSLF). However, the mechanisms mediating the action of the CS in hepatic fibrosis are unclear. The present study hypothesized that Schistosoma J. infection upregulates cannabinoid receptor 1 (CBI) due to activation of NADPH oxidase leading to a fibrotic phenotype in hepatic stellate cells (HSCs). The SSLF model was developed by infecting mice with Schistosoma J. cercariae in the skin, and HSCs from control and infected mice were then isolated, cultured, and confirmed by analysis of HSC markers alpha-SMA and desmin. CBI significantly increased in HSCs isolated from mice with SSLF, which was accompanied by a greater expression of fibrotic markers alpha-SMA, collagen I, and TIMP-1. CB1 upregulation and enhanced fibrotic changes were also observed in normal HSCs treated with soluble egg antigen (SEA) from Schistosoma J. Electron spin resonance (ESR) analysis further demonstrated that superoxide (O-2(center dot-)) production was increased in infected HSCs or normal HSCs stimulated with SEA. Both Nox4 and Noxl siRNA prevented SEA-induced upregulation of CBI, alpha-SMA, collagen I, and TIMP-1 by inhibition of O-2(center dot-) production, while CBI siRNA blocked SEA-induced fibrotic changes without effect on O-2(center dot-) production in these HSCs. Taken together, these data suggest that the fibrotic activation of HSCs on Schistosoma J. infection or SEA stimulation is associated with NADPH oxidase-mediated redox regulation of CBI expression, which may be a triggering mechanism for SSLF. (C) 2014 Elsevier Inc. All rights reserved.