Scientific efforts have been made for a better understanding of the pathogenesis of hepatocellular carcinoma (HCC). We investigated the possible role of miR-192/nuclear factor-kB (NF-kB)/transforming growth factor-ß (TGF-ß)/E-cadherin in hepatic tumorigenesis. We expected a modulatory impact of thymoquinone. Thirty adult male rats were assigned into 3 groups (n 5 10); (1) Control group. Group (2): Experimental HCC induced by intraperitoneal injection of diethylnitrosamine (DENA) followed by carbon tetrachloride (CCl4). Group (3): Thymoquinone 20 mg kg 1/oral supplementation starting from the model induction to the end of the 8th week. The HCC (DENA-CCL4) model was confirmed by elevated serum levels of alpha-fetoprotein and transaminases (ALT, AST) and by histopathological examination which denoted marked cellular atypia and features of neoplasia. Suppressed hepatic miR-192 and E-cadherin expression were detected in the HCC (DENA-CCL4) group accompanied by elevated tumor necrosis factor (TNF-á), interleukin (IL6)/NF-kB & TGF-ß1. Thymoquinone treatment protected the rat livers from hepatic tumorigenesis. Thymoquinone diminished (P < 0.001) alpha-fetoprotein and improved ALT, AST. It preserved hepatic miR-192 and normal E-cadherin expression. Thymoquinone-treated rats showed abrogated TNF-á, IL6/NF-kB/TGF-ß. Thymoquinone increased cell apoptosis markers Bax/Bcl2 and diminished cellular atypia. Pearson's correlations revealed positive association between miR-192 expression and E-cadherin and Bax/Bcl2 as well, and it was negatively correlated to alpha-fetoprotein, NF-kB and TGF-ß and the cellular atypia score. In conclusion, thymoquinone protected the liver tissues through preserving miR-192 and E-cadherin and aborting NF-kB & TGF-ß signaling. The current results highlight a new role for thymoquinone in preventing hepatic tumorigenesis. Kulcsszavak: hepatocellular carcinoma, thymoquinone, microRNA-192, NF-kB, TGF-ß, E-cadherin