Targeting peroxiredoxin 2 prevents hepatocarcinogenesis in metabolic liver disease models

Chronic liver disease and hepatocellular carcinoma are a global health burden, causing approximately two million deaths globally per year. Treatment options for advanced liver disease are limited and strategy to prevent hepatocellular carcinoma (HCC) development are lacking. Peroxiredoxin 2 (PRDX2) PRDX2 is a soluble cellular enzyme that detoxify peroxides generated during oxidative stress. This protein is involved in the control of various physiological process including cell growth and differentiation by regulating numerous signaling pathways. PRDX2 was also reported to promote tumor growth including colorectal and breast cancers. Since its role in liver disease progression and HCC development is unknown, we therefore further explored the role of PRDX2. This study aims to understand the mechanistic events of Prdx2 KO on the cell circuits driving metabolic liver disease progression and HCC development. We induced a liver-specific Prdx2 KO in a Cas9 transgenic mouse model for NASH and HCC. Prdx2 gene was specifically targeted in hepatocytes by combining a Cre-dependent expression of the Cas9 endonuclease in the liver and the hepatic delivery of specific single guide (sg) RNA to hepatocytes using Adeno-associated virus 8 (AAV8) as vector. Chronic liver disease and HCC were thereafter induced by a single dose of diethylnitrosamine (DEN), followed by a 6-month choline-deficient L-amino acid-defined high-fat diet (CDAHFD). At the time of sacrifice, animals were anesthetized, weighted and a terminal blood collection was performed by cardiac puncture. Total RNA from mice liver were obtained using Tri Reagent (MRC) and Direct-zol RNA Miniprep kit (Zymo Research).