Ibrahim, Samar SalahFahim, Sally ATadros, Samer ABadary, Osama A2022-04-232022-04-2301/04/2022https://doi.org/10.1002/jbt.23078http://repository.msa.edu.eg/xmlui/handle/123456789/4920Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer‐related death globally. Chemoprevention is the most effective technique for reducing HCC incidence. Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, exhibits anti‐inflammatory and antineoplastic activities against various cancers. Therefore, TQ was tested as an inhibitor of the initial phase of diethylnitrosamine (DEN)‐induced HCC in rats. Twenty‐four male Wistar albino rats were randomly placed into four equal groups. Group 1 received saline and acted as the negative control; Group 2 received TQ; Group 3 received DEN; and Group 4 received TQ for 7 days and DEN on the 8th day. After 24 h of fasting, blood samples were taken from the slaughtered rats. Additionally, each rat's liver was dissected and separated into two halves for histological and biochemical investigation. DEN‐induced hepatotoxicity was detected by elevated hepatic enzymes and HCC biomarkers reduced antioxidant and proapoptotic statuses. DEN administration caused a significant increase in the levels of glutathione, superoxide dismutase, malondialdehyde, caspase‐3, alpha‐fetoprotein (AFP), AFPL3, glypican 3, and the expression of BAX. However, DEN significantly decreased glutathione peroxidase, catalase, and CYP2E1 and the expression of BCl‐2. Furthermore, it caused histological changes and showed a strong positive GSH S‐transferase P expression in the hepatic parenchyma. Pretreatment with TQ prevented the histopathological and most of the biochemical changes and improved the antioxidant status. TQ supplementation appears to suppress the development of DEN‐initiated liver cancer by reducing oxidative stress, activating the intrinsic mitotic apoptosis pathway, and retaining the antioxidant enzymesen-USdiethylnitrosaminehepatocellular carcinomainitiation stageprotectivethymoquinoneArticlehttps://doi.org/10.1002/jbt.23078