A wide variety of natural products have powerful chemopreventive effects due to their antioxidant, antimutagenic, and anti-inflammatory activities that enable them to arrest cell proliferation in several cancer models. In the present study, we shed light on the protective mechanism of Nigella sativa extract against diethylnitrosamine (DENA)-induced preneoplastic stage of hepatocellular carcinoma (HCC) in rats. We studied the extract effect on EGFR/ERK1/2 signaling pathway as one of the major signaling pathways controlling cell proliferation during hepatocarcinogenesis as well as the investigation of its antioxidant activity. The study also compared the effects of NSEE to those of (thymoquinone) TQ and silymarin as hepatoprotective substances. Rats received daily doses of NSEE (150, 250, 350 mg/kg BW), a dose per three alternative days/week of TQ (20 mg/kg BW) and a daily dose of silymarin (100 mg/kg BW). The doses were administered orally by gavage for 12 days before DENA and CCl administration, and then the supply of NSEE, TQ or silymarin was continued until the end of the experiment (16 weeks). DENA administration activated EGFR/ERK1/2 signaling and caused a significant increase in P-EGFR and P-ERK1/2 as well as a significant up-regulation of expression of target genes such as PCNA, c-fos and Bcl2, which indicated the increase in cell proliferation. Furthermore, a significant elevation in alpha-fetoprotein (AFP) and hepatic enzymes was observed in DENA-treated rats in addition to a decrease in the antioxidant status. The protection with NSEE, TQ, or silymarin has the potential to inhibit the EGFR/ERK1/2 activation and improve the antioxidant status. Moreover, the action of NSEE against the hepatocarcinogenesis was supported by high antioxidant activity and the histopathological observations of the liver. These data suggest that NSEE has a chemopreventive role in DENA-induced HCC through the inhibition of the EGFR/ERK1/2 signaling pathway and their target genes in addition to its role as an antioxidant.

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