Abstract
Liver cancer is the most common cause of cancer death worldwide, causing about 866,136 deaths in 2022. Several studies illustrate that constitutive nuclear factor-κB (NF-κB) activity plays a central role in the hepatic neoplastic progression, and its inhibition in hepatocytes retards and reduces the development of hepatocellular carcinoma. A recent study revealed that Metformin, a hypoglycemic agent used to treat patients with type 2 diabetes mellitus (T2DM), has significantly reduced the incidence of hepatocellular carcinoma (HCC) studied in a transgenic mouse model (TG221 strain). As NF-κB plays a key role in the development of insulin resistance, intervention with Metformin could reduce the risk of neoplastic transformation of hepatocytes. To decipher the interlink between type 2 diabetes and reduced incidence of hepatic carcinoma mediated by Metformin, we performed a systems biology study and identified a hub protein playing a crucial role in the above-said mechanism. The results suggested an association between a network of proteins in the disease mechanism and Protein kinase B (AKT1), a serine-threonine-specific kinase, as a hub protein. Molecular docking and molecular dynamics simulation studies identified the specific interactions of the tested molecules with the hub protein, thereby encouraging further studies to assess protein kinase B as a novel biomarker for hepatocellular carcinoma. While the present findings provide mechanistic insights into Metformin's antitumor effects in an insilico condition, translation of these findings to preclinical systems and to human HCC requires validation in human tissues and patient cohorts.