The study investigates the role of the transcription factor Carbohydrate-responsive element binding protein (ChREBP) in liver carcinogenesis, particularly in hepatocellular carcinoma (HCC). ChREBP is found to be upregulated in HCC and is associated with poor prognosis. Overexpression of ChREBP in mice leads to the development and progression of HCC, driven by enhanced PI3K/AKT signaling and metabolic rewiring. ChREBP activates the PI3K regulatory subunit p85α, which stabilizes and inactivates the p10 catalytic subunit of PI3K, thereby enhancing PI3K/AKT signaling. Additionally, ChREBP reroutes glucose and glutamine metabolic fluxes towards de novo nucleotide and fatty acid synthesis, supporting cell proliferation. The study also identifies a positive feedback loop where ChREBP-mediated p85α expression amplifies PI3K/AKT signaling and HK2 expression, further enhancing ChREBP activity. Finally, pharmacological inhibition of ChREBP with SBI-993 significantly suppresses HCC tumor growth in vivo, suggesting that targeting ChREBP could be a promising therapeutic approach for HCC treatment.The study investigates the role of the transcription factor Carbohydrate-responsive element binding protein (ChREBP) in liver carcinogenesis, particularly in hepatocellular carcinoma (HCC). ChREBP is found to be upregulated in HCC and is associated with poor prognosis. Overexpression of ChREBP in mice leads to the development and progression of HCC, driven by enhanced PI3K/AKT signaling and metabolic rewiring. ChREBP activates the PI3K regulatory subunit p85α, which stabilizes and inactivates the p10 catalytic subunit of PI3K, thereby enhancing PI3K/AKT signaling. Additionally, ChREBP reroutes glucose and glutamine metabolic fluxes towards de novo nucleotide and fatty acid synthesis, supporting cell proliferation. The study also identifies a positive feedback loop where ChREBP-mediated p85α expression amplifies PI3K/AKT signaling and HK2 expression, further enhancing ChREBP activity. Finally, pharmacological inhibition of ChREBP with SBI-993 significantly suppresses HCC tumor growth in vivo, suggesting that targeting ChREBP could be a promising therapeutic approach for HCC treatment.