Xanthophyll β‐Cryptoxanthin Inhibits Highly Refined Carbohydrate Diet–Promoted Hepatocellular Carcinoma Progression in Mice

β-Cryptoxanthin (BCX) can be cleaved by both β-carotene 15,15'-oxygenase (BCO1) and β-carotene 9',10'-oxygenase (BCO2), generating biological active vitamin A and apocarotenoids. We examined whether BCX feeding could inhibit diethylnitrosamine (DEN)-initiated, highly refined carbohydrate diet (HRCD)-promoted hepatocellular carcinoma (HCC) development, dependent or independent of BCO1/BCO2 activity.Two-week-old male wild-type (WT) and BCO1-/- /BCO2-/- double knockout (DKO) mice are given a single intraperitoneal injection of DEN (25 mg kg-1 body weight) to initiate hepatic carcinogenesis. At 6 weeks of age, all animals are fed HRCD (66.5% of energy from carbohydrate) with or without BCX for 24 weeks. BCX feeding increases hepatic vitamin A levels in WT mice, but not in DKO mice that shows a significant accumulation of hepatic BCX. Compared to their respective HRCD littermates, both WT and DKO fed BCX have significantly lower HCC multiplicity, average tumor size, and total tumor volume, and the steatosis scores. The chemopreventive effects of BCX are associated with increased p53 protein acetylation and decreased protein levels of lactate dehydrogenase and hypoxia-inducible factor-1α in tumors.This study suggests that BCX feeding may alleviate HRCD-promoted HCC progression by modulating the acetylation of p53, hypoxic tumor microenvironment, and glucose metabolism, independent of BCO1/BCO2.