Abstract 4159: Investigating the role of Akt isoforms in hepatocellular carcinoma and liver fibrosis

Abstract Liver fibrosis and hepatocellular carcinoma (HCC) are major global health issues, with HCC being the most common primary liver cancer and a leading cause of cancer-related death. Metabolic dysfunction-associated steatohepatitis (MASH) is an emerging risk factor for HCC. Theserine/threonine protein kinase Akt plays a central role in cell survival, growth, and metabolism, and its hyperactivation via the PI3K/Akt pathway is implicated in many cancers. Mammalian cells express three Akt isoforms, but the effects of isoform-specific Akt inhibition remain poorly understood. We previously showed that global deletion of Akt2 along with hepatic deletion of Akt1 surprisingly leads to early onset of spontaneous HCC. The current study investigates the mechanisms underlying spontaneous HCC in these mouse models and examines the roles of Akt1 and Akt2 in MASH-induced liver fibrosis and HCC. Two mouse strains were generated: Akt2-/-; Akt1hep-/- and Akt1-/-; Akt2hep-/-. Akt2-/- mice survived hepatic Akt1 deletion, but all developed early onset HCC with elevated insulin and glucose levels, increased lipid droplet accumulation, and CD36 expression. In contrast, Akt1-/- mice survived hepatic Akt2 deletion without tumor development and had normal glucose levels. These findings suggest that HCC development in Akt2-/-; Akt1hep-/- mice occurs despite the loss of Akt activity, likely due to compensatory mechanisms or alternative pathways in hepatocarcinogenesis. Given the high insulin and glucose levels in Akt2-/-; Akt1hep-/- mice, we hypothesize that reducing insulin levels may prevent HCC. Additionally, we are examining whether CD36 is essential for HCC development in these mice. The second part of this study explores the impact of Akt isoforms on MASH-induced liver fibrosis and HCC. We have generated five mouse groups (Akt1-/-, Akt2-/-, Akt1hep-/-, Akt2hep-/-, andAkt1hep-/-; Akt2hep-/-), and these are fed with Western diet and subject to weekly CCl4 injections for MASH induced HCC. This model will help to understand the role of Akt1 or Akt2 upon hepatic versus systemic deletion and its effect on liver fibrosis and HCC progression in the MASH-induced model. Together, these studies will provide insights into the isoform-specific roles of Akt in liver carcinogenesis and fibrosis, with implications for targeted therapies in HCC. Citation Format: Manahil Ghazi, Ahmed Abd El Razek, Nissim Hay. Investigating the role of Akt isoforms in hepatocellular carcinoma and liver fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4159.