Volume 5 Number 1 2023
In Silico Repurposing of FDA-approved Drugs Targeting Keap1-NRF2 Axis in Hepatocellular Carcinoma for Precision Therapy
Amena Khatun Manica1*, Tufael2, Md Abu Bakar Siddique3, Most Farhana Akter4, Md. Robiul Islam4
Journal of Precision Biosciences 5 (1) 1-8 https://doi.org/10.25163/biosciences.5110436
Submitted: 27 June 2023 Revised: 30 August 2023 Accepted: 05 September 2023 Published: 07 September 2023
Abstract
Background: The Keap1-NRF2 signaling pathway plays a critical role in regulating cellular redox homeostasis and has been identified as a major contributor to drug resistance in cancers such as hepatocellular carcinoma (HCC). Hyperactivation of this pathway enhances antioxidant responses in cancer cells, thereby reducing the effectiveness of chemotherapy and accelerating disease progression.
Objective: This study investigates the repurposing potential of three FDA-approved multi-kinase inhibitors-Regorafenib, Sorafenib, and Lenvatinib-as modulators of the Keap1-NRF2 pathway in the context of HCC.
Methods: The three-dimensional structure of wild-type Keap1 and two clinically relevant mutants (G364S, D422H) were retrieved and optimized for molecular docking. Ligand preparation, energy minimization, and flexible docking were conducted using PyRx (AutoDock Vina). Gene co-expression, GO enrichment, Reactome pathway mapping, and PPI analysis were performed using GEPIA2, STRING, Enrichr, and DAVID databases. Toxicity prediction was assessed using ProTox-II.
Results: Among all ligands, Regorafenib exhibited the strongest binding affinity (-10.7 kcal/mol) to the ETGE-binding cleft of Keap1 and maintained stable interactions with key residues. Mutational analysis revealed that binding affinity decreases in mutant forms. Co-expression analysis confirmed an inverse correlation between Keap1 and NRF2 expression in HCC. Enrichment analyses identified strong associations with oxidative stress response and detoxification pathways. Toxicity predictions showed Regorafenib and Sorafenib to be moderately hepatotoxic, whereas Lenvatinib demonstrated a safer profile.
Conclusion: This in silico study highlights Regorafenib as a strong candidate for Keap1-targeted repurposed therapy in HCC. Further in vitro and in vivo validation is recommended to confirm its therapeutic relevance in NRF2-dysregulated cancers.
Keywords: Keap1-NRF2 pathway, Hepatocellular carcinoma (HCC), Drug repurposing, Molecular docking, Redox homeostasis.
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