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Therapeutic interventions are still limited in the treatment of liver fibrosis even though an incredible number of publications related to silymarin are produced. This is due to the complex molecular pathogenesis. Several studies pointed to the role of renin-angiotensin system (RAS) in hepatic fibrogenesis. Therefore, the present study was designed to examine the effect of the combination of lisinopril (LIS) with silymarin (SIL) on CCl4-induced hepatic fibrosis along with an in-vitro confirmatory experiment. Rats were treated with LIS (1 mg kg−1) and SIL (30 mg kg−1) as a single agent and as combined to LIS (1 mg kg−1). Our results revealed that down-regulation of NFκBp65 mRNA expression and inhibition of phosphorylation of NFκBp65 (at Ser536) and NFκBia were implicated in the anti-fibrotic effect of both LIS and SIL. Consequently lower levels of NFκB-induced TNF-α, TGF-β1, MMP-2, TIMP-1 and VEGF compared to control group. In addition, levels of α-SMA protein expression and hydroxyproline are decreased in association with marked improvement in liver function, oxidative stress markers and histological picture. In addition, LIS augmented the inhibitory effect of SIL on NFκB pathway at lower dose level. We concluded that LIS, via targeting NFκB pathway, increases anti-oxidant capacity of liver tissue and exhibits anti-inflammatory, anti-fibrotic and anti-angiogenic activity and augments sensitivity to SIL. Therefore, LIS is a promising candidate for further clinical investigation in the treatment of liver fibrosis.The proposed mechanism of action for silymarin and lisinopril in interfering with NFκB pathway. DAG, diacyl glycerol; IkB, inhibitory kappa B protein; IKK, IκB kinase; MMP-2, matrix metalloproteinase 2; NFkB, nuclear transcription factor kappa B; PKC, protein kinase C; PLC, phospholipase C; TGF-β, transforming growth factor beta; TIMP-1, tissue inhibitor of metalloproteinase 1; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.Lisinopril and silymarin down-regulated NFκBp65 mRNA expression.Lisinopril and silymarin inhibited phosphorylation of NFκBp65 (at Ser536) and NFκBia.Lisinopril and silymarin down-regulated α-SMA protein expression.Lisinopril and silymarin demonstrated anti-inflammatory and anti-angiogenic activity.Lisinopril and silymarin increased anti-oxidant capacity of liver tissue.