L-ascorbate prevents non-alcoholic steatohepatitis-based hepatocarcinogenesis in Sod1/Prdx4 double-knockout mice

Abstract Superoxide dismutase 1 (Sod1) and peroxiredoxin 4 (Prdx4) double knockout (DKO) causes symptoms similar to non-alcoholic steatohepatitis (NASH) even at younger ages. This study revealed that DKO mice exhibited high mortality, and surviving DKO mice developed hepatocellular carcinoma within the first year of life. Administration of physiological doses of L-ascorbate (1.5 mg/mL) in drinking water reduced mortality and effectively prevented tumor development. Oxidative stress due to SOD1 deficiency and endoplasmic reticulum stress due to PRDX4 deficiency may promote NASH, ultimately leading to hepatocarcinogenesis. Analyses of liver tissues from 8-month-old DKO mice revealed that ascorbate supplementation robustly suppressed upregulation of amino acid metabolic pathways observed in DKO mice. These findings suggest that upregulation of amino acid metabolic pathways may be important for the hepatocarcinogenesis. An iron-regulatory protein and aconitase activity were decreased in DKO mice regardless of ascorbate status. Furthermore, precancerous lesions were more reactive to a ferroptosis-specific antibody than tumor lesions. These results suggest that ascorbate supplementation and aberrant iron metabolism selectively induce the death of cells that lead to tumorigenic proliferation at the precancerous stage. Adequate intake of ascorbate in daily life may improve the tumorigenic process promoted by hepatic steatosis due to oxidative insult.