Application of comprehensive bioinformatics approaches to reconnoiter crucial genes and pathways underpinning hepatocellular carcinoma: a drug repurposing endeavor.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm in the world. Chronic inflammation of liver and associated wound healing processes collectively contribute to the development of cirrhosis which further progresses to dysplastic nodule and then to HCC. Etiological mediators and ongoing manipulations at cellular level in HCC are well established; however, key protein interactions and genetic alterations involved in stepwise hepatocarcinogenic pathways are seldom explored. This study aims to unravel novel targets of HCC and repurpose the FDA-approved drugs against the same. Genetic data pertinent to different stages of HCC were retrieved from GSE6764 dataset and analyzed via GEO2R. Subsequently, protein-protein interaction network analysis of differentially expressed genes was performed to identify the hub genes with significant interaction. Hub genes displaying higher interactions were considered as potential HCC targets and were validated thorough UALCAN and GEPIA databases. These targets were screened against FDA-approved drugs through molecular docking and dynamics simulation studies to capture the drugs with potential activity against HCC. Finally, cytotoxicity of the shortlisted drug was confirmed in vitro by MTT assay. CDC20 was identified as potential druggable target. Docking, binding energy calculations, and dynamic studies revealed significant interaction exhibited by Labetalol with CDC20. Further, in MTT assay, Labetalol demonstrated an IC50 of 200.29 µg/ml in inhibiting the cell growth of HepG2 cell line. In conclusion, this study discloses a series of key genetic underpinnings of HCC and recommends the pertinence of labetalol as a potential repurposable drug against HCC.