Diet-induced obesity impairs lipid metabolism and results in triglyceride storage by adipocytes, adipose tissue inflammation and excess of free fatty acids which aggravates adipose tissue dysfunction. The adipose tissue inflammation predisposes to insulin resistance that eventually leads to increased insulin-like growth factor (IGF-Ι). It is also likely to be associated with additional hepatocyte damage, including parenchymal inflammation, hepatocytic degeneration, liver fibrosis and cirrhosis in response to an oxidative-stress state. On the other hand, non-alcoholic steato-hepatitis (NASH) exhibits an increased risk for developing cirrhosis, liver failure and even hepatocellular carcinoma (HCC). However, caloric restriction (CR) has been shown to increase longevity in multiple species and exert inhibitory effects against a variety of spontaneous tumors in several experimental model systems. Our present study aimed to further explore the possible potential role of food modification in the pathogenesis of induced hepatocellular carcinoma. An experimental model of HCC was induced by intra-peritoneal injection of diethylnitrosamine (DEN), followed by a single subcutaneous injection of carbon-tetrachloride (CCl4) once weekly for 6 weeks. Study groups included: a group of normal control rats (vehicle-treated) and main second experimental group of rats in which hepatocellular-carcinoma was induced chemically. All animals were left for a period of 6 weeks which was the time needed for the pathogenesis of the disease. During this period, the experimental animals in the main experimental group were randomly subdivided into the following: a) group of induced-HCC, b) induced-HCC group of animals which were supplied with a diet restricted to 75% of that given to controls, c) a group of induced-HCC rats which were supplied with the former diet restriction and receiving orally COX2 inhibitor (celecoxib), d) induced-HCC group which received a high fat-diet in which 40% of its calories was fat-derived and lastly e) a group of induced-HCC animals receiving the former consistency of the high fat diet and was supplied orally with COX2 inhibitor (celecoxib). Results of the present study revealed that the enhanced serum IGF-Ι levels estimated in the induced-HCC rats were associated with a significant increase in COX-2 and IL-6 gene expression as well as acceleration of pathological changes in the liver, especially after receiving high fat-diet (HFD). Increased serum levels of IGF-ΙΙ and alpha-fetoprotein (AFP) were also significantly decreased in CR as well as CR treated with celecoxib -groups. Thus, we conclude that, there is a strong positive correlation which links food composition with the onset of hepatocellular carcinoma.