Hepatocellular carcinoma (HCC) accounting about 75% of hepatic neoplasia, making it the most common kind
of liver cancer worldwide. So, this study was planned to evaluate the beneficial chemopreventive efficacy of
hesperidin (Hes) in experimental model of Diethyl nitrosamine (DEN) / Carbon tetrachloride (CCl4) –induced
HCC in rats. Thirty male rats were divided into 3 equal groups. Group 1 (normal control): rats didn't receive any
treatment. Group 2 (HCC): HCC was induced in rats by injection of DEN (200mg/kg b.w/i.p), then 2 weeks later of
DEN injection rats received 3 weekly successive doses of CCl4 (3ml/kg b.wt/ orally) at 1:1 dilution in corn oil as a
promoter of carcinogenic effect. DEN and CCl4 administration were repeated once again after 5 weeks. Group 3
(HCC+ hesperidin): 15 weeks after HCC induction, rats treated with Hes (150 mg/kg b.wt), orally and continued
for 6 weeks. A significant increase in serum ALT, AST and ALP activities were observed in HCC-induced rats.
However, significant downregulation of liver Nrf2, Caspase-3, Bcl-2 and MicroRNA-34a with upregulation of
FGF-2 and MicroRNA-221 with Global DNA hyper-methylation were observed in HCC group. Hesperidin treat-
ment exhibited downregulation of microRNA-221 and FGF-2 with upregulation of Nrf2, Bcl-2, caspase 3 gene
and Global DNA hypo-methylation. Interestingly, improvement of liver histopathological alterations supported
the chemopreventive activity of Hesperidin. Conclusively, Hesperidin ameliorates the progression of HCC and
has promising chemopreventive, and antiangiogenic activity, inhibiting growth promoting oncogene and initia-
tion of gene regulating apoptosis and protects the liver from oxidative damage and inflammation.