FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for -mutated HCC.

Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/β-catenin pathway.

Highlights d PKCl/i levels negatively correlate with HCC histological tumor grade d PKCl/i-deficient hepatocytes promote HCC linked to increased ROS and NRF2 activation d PKCl/i represses autophagy directly and inhibits OXPHOS to restrain ROS and NRF2 d Increased ROS and NRF2 by PKCl/i deficiency accounts for increased HCC

Apc ko-liv mice, the methionine-and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors. CONCLUSIONS: In mice and humans, HCCs with mutations that activate b-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18 F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress b-catenin.

Excessive glucose production by the liver is a key factor in the hyperglycemia observed in type 2 diabetes mellitus (T2DM). Here, we highlight a novel role of liver kinase B1 (Lkb1) in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect is observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion is associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic, proteomic and pharmacological approaches, we identify the aminotransferases and specifically Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.

CTNNB1 (catenin beta 1)-mutated hepatocellular carcinomas (HCCs) account for a large proportion of human HCCs. They display high levels of respiratory chain activity. As metabolism and redox balance are closely linked, tumor cells must maintain their redox status during these metabolic alterations. We investigated the redox balance of these HCCs and the feasibility of targeting this balance as an avenue for targeted therapy. We assessed the expression of the nuclear erythroid 2 p45-related factor 2 (NRF2) detoxification pathway in an annotated human HCC data set and reported an enrichment of the NRF2 program in human HCCs with CTNNB1 mutations, largely independent of NFE2L2 (nuclear factor, erythroid 2 like 2) or KEAP1 (Kelch-like ECH-associated protein 1) mutations. We then used mice with hepatocyte-specific oncogenic β-catenin activation to evaluate the redox status associated with β-catenin activation in preneoplastic livers and tumors. We challenged them with various oxidative stressors and observed that the β-catenin pathway activation increased transcription of Nfe2l2, which protects β-catenin-activated hepatocytes from oxidative damage and supports tumor development. Moreover, outside of its effects on reactive oxygen species scavenging, we found out that Nrf2 itself contributes to the metabolic activity of β-catenin-activated cells. We then challenged β-catenin activated tumors pharmacologically to create a redox imbalance and found that pharmacological inactivation of Nrf2 was sufficient to considerably decrease the progression of β-catenin-dependent HCC development. Conclusion:These results demonstrate cooperation between oncogenic β-catenin signaling and the NRF2 pathway in CTNNB1mediated HCC tumorigenesis, and we provide evidence for the relevance of redox balance targeting as a therapeutic strategy in CTNNB1-mutated HCC. (Hepatology Communications 2021;0:1-17).T umorigenesis is a complex process involving multiple modifications promoting proliferation and preventing cell death. The maintenance of neoplastic cell proliferation and growth requires a metabolic rewiring to provide essential macromolecules and energy. (1) Since the first observations that tumor cells displayed higher glucose consumption through a glycolytic pathway, it has been shown that there are numerous metabolic pathways, from enhanced glutaminolysis to increased fatty acid oxidation, that can be altered to favor tumor survival and progression. (2)(3)(4) Although altering their metabolic activity, tumor cells also have to maintain a redox status compatible with survival, as metabolism and redox balance are closely linked-mostly through the production

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A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22104-4