# Unraveling a novel therapeutic facet of Etravirine to confront Hepatocellular Carcinoma via disruption of cell cycle

## TL;DR

This study explores Etravirine, an HIV drug, as a potential treatment for liver cancer by targeting cell cycle regulators.

## Contribution

Etravirine is identified as a novel candidate for HCC treatment through repurposing and targeting CDK2.

## Key findings

- Etravirine showed cytotoxic effects in Huh-7 liver cancer cells.
- Etravirine inhibited CDK2, disrupting the cell cycle in Huh-7 cells.
- Molecular docking identified Etravirine as a potential CDK2 inhibitor.

## Abstract

Hepatocellular Carcinoma (HCC) is a malignancy with high mortality rates and limited treatment options. This study aimed to unearth the repurposable potential of FDA-approved drugs against specific genetic targets governing the HCC pathological pathways. The transcriptomics microarray datasets were explored to retrieve the HCC specific differentially expressed genes, and the significant genes were fed in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database to capture the protein-protein interactions, which were visualized in Cytoscape. This revealed CCNA2, a cell cycle regulator, as a potential target, which mediates its action by interacting with CDK1 and CDK2. Further, with the intention of identifying inhibitors for CDK1 and CDK2, a drug library was created, and the drugs were virtually screened against their respective targets via molecular docking and dynamics studies. This captured the binding affinity of Steviolbioside towards CDK1 and Etravirine and Fludarabine towards CDK2. In vitro, validation confirmed the cytotoxic potential of Etravirine and Fludarabine in Huh-7 cell lines. Further, enzymatic assays, gene expression analysis, and cell cycle analysis signified the anti-proliferative potential of Etravirine in Huh-7 cells via inhibition of CDK2. In this drug repurposing venture, Etravirine, a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV, emerged as a promising candidate for HCC treatment. The findings warrant further preclinical and clinical investigations to ascertain the repurposable potential of Etravirine against HCC, particularly in patients with viral infections.