1 Vol.:(0123456789) Scientifc Reports | (2022) 12:15648 | https://doi.org/10.1038/s41598-022-19854-6 www.nature.com/scientificreports Integrated analysis to study the interplay between post‑translational modifcations (PTM) in hepatitis C virus proteins and hepatocellular carcinoma (HCC) development Aqsa Ikram 1* , Bisma Rauf 2 , Badr Alzahrani 3 , Faryal Mehwish Awan 4 , Ayesha Obaid 4 , Anam Naz 1 , Salik Javed Kakar 5 & Hussnain Ahmed Janjua 5* Many PTMs dysregulation is known to be the major cause of many cancers including HCV induced HCC. PTMs of hepatitis C virus (HCV) regions NS3/4A, NS5A and NS5B are crucial for proper protein functions and replication that directly afect the generation of infectious virus particles and completion of its life cycle. In this study, we have performed comprehensive analysis of PTMs within HCV non‑structural proteins (NS3/4A, NS5A and NS5B) through bioinformatics analysis to examine post‑translational crosstalk between phosphorylation, palmitoylation, methylation, acetylation and ubiquitination sites in selected viral proteins. Our analysis has revealed many highly putative PTMs sites that are also conserved among major genotypes conferring the importance of these sites. We have also analysed viral 3D structures in their modifed and unmodifed forms to address extent and signatures of structural changes upon PTM. This study provides evidence that PTMs induce signifcant conformational changes and make viral proteins more stable. To fnd the potential role of PTMs in HCV induced HCC, docking analysis between selected viral proteins and p38‑MAPK has been performed which also confrms their strong association with HCV induced HCC. The major fndings proposed that PTMs at specifc sites of HCV viral proteins could dysregulate specifc pathways that cause the development of HCC. Hepatitis C virus (HCV) is a positive sense RNA virus. It belongs to the family Flaviviridae 1 . It develops chronic infection in humans that leads to hepatic failure 2 . So far, the only HCV treatment is combination therapy of pegylated interferon and ribavirin (PEG/RBV), however, direct-acting antivirals (DAAs) has initiated the era of well-tolerated medications 3 . Tough these treatments are efective but still encounter certain limitations includ- ing drug resistance, mutations and side efects 4 . Hence, for the development of an efcient antiviral treatment, comprehensive knowledge of viral pathogenesis is essential. Post-translational modifcations (PTMs) are covalent interactions that occur either as a result of addition of modifying groups or by proteolytic cleavage that ultimately alters the main properties of proteins. Addition of simple chemical groups include acetyl, hydroxyl, methyl, or phosphate groups, however, addition of more com- plex groups include AMP, ADP-ribose, lipids, sugars and small polypeptides like ubiquitins 5 . PTMs are known to provide essential insights of various cellular functions 6 , including protein–protein interactions, their localization and turnover. In addition, PTMs are substantial approaches that can be used by many pathogens, both by viruses and bacteria, to control host factors that are important for their infection 7 . Viruses rely on the protein synthesis OPEN 1 Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore, Pakistan. 2 Department of Biomedical Engineering, UET Lahore, Narowal campus, Narowal, Pakistan. 3 Department of Clinical Laboratory Sciences, Jouf University, Sakaka, Saudi Arabia. 4 Department of Medical Lab Technology, University of Haripur (UOH), Haripur, Pakistan. 5 Atta Ur Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan. * email: aqsa.ikram@imbb.uol.edu.pk; janjua.hussnain@gmail.com; principal.asab@nust.edu.pk