Integrative Analysis of Molecular Interactions and Repurposable Drugs in Primary Biliary Cholangitis
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Computational validation, cytokine signaling, drug repurposing, hub genes, primary biliary cholangitisAbstract
Introduction: Primary Biliary Cholangitis (PBC) is an autoimmune liver disease characterized by chronic destruction of intrahepatic bile ducts, leading to fibrosis and eventual liver failure. Current first-line treatments, including ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), provide insufficient therapeutic benefit for a substantial proportion of patients. Integrative systems-level analyses of multi-omic data enable the identification of potential therapeutic targets and the repurposing of existing drugs.
Methods: A total of 214 human genes associated with PBC were retrieved from NCBI Gene and DisGeNET databases. Protein-protein interaction (PPI) networks were constructed using STRING and subsequently analyzed for hub genes and network clusters using Cytoscape. Pathway enrichment analysis was performed using Reactome, and drug-gene associations were evaluated using the DSigDB database. Selected drug-target interactions were further assessed using experimentally validated binding data from BindingDB and molecular docking results generated by SwissDock.
Results: The network analysis produced 187 nodes which connected through 1,645 edges. Hub gene analysis highlighted TP53, IL6, CXCL8, STAT3, IFNG, JUN, and CDKN1A as central regulators of immune and apoptotic signaling pathways. The Reactome analysis showed that interleukin and TP53-mediated pathways achieved statistical significance at an FDR value of less than 0.05. The FDA has approved six compounds for medical use including Simvastatin and Budesonide and Tocilizumab and N-acetylcysteine and PD98059 and Vorinostat which demonstrate supportive experimental or computational evidence of target engagement.
Conclusion: This integrative network-based framework identified central molecular regulators and repurposable drugs for PBC. Further experimental and clinical studies are required to determine the therapeutic potential of these candidates in autoimmune liver disease.
References
Rawashdeh B, Couillard A, Rawshdeh A, Aziz H, Esteban J, Selim M. Primary biliary cholangitis, liver transplantation, and hepatocellular carcinoma: A mini-review. Gene Expr. 2022;21(2):34-40. https://doi.org/10.14218/GE.2022.00016.
Reshetnyak VI, Vinnitskaya EV, Maev IV. Primary biliary cholangitis: A historical perspective from xanthomatous lesions to modern molecular biology. World J Gastrointest Pathophysiol. 2025;16(2). https://doi.org/10.4291/wjgp.v16.i2.107347
Kim KA. Diagnosis and treatment of primary biliary cholangitis. Korean J Gastroenterol. 2023;81(2):86-90. https://doi.org/10.4166/kjg.2023.002.
Cheung A, LaRusso N, Gores G, Lazaridis K. Epigenetics in the primary biliary cholangitis and primary sclerosing cholangitis. Semin Liver Dis. 2017;37(2):159-174. https://doi.org/10.1055/s-0037-1603324.
Li Y, Tang R, Ma X. Epigenetics of Primary Biliary Cholangitis. In: Gershwin ME, Vierling JM, Manns MP, editors. Liver immunology: Principles and practice. Cham: Springer; 2020. p. 259-83. https://doi.org/10.1007/978-981-15-3449-2_10
Xie YQ, Ma HD, Lian ZX. Epigenetics and primary biliary cirrhosis: a comprehensive review and ımplications for autoimmunity. Clin Rev Allergy Immunol. 2016;50(3):390-403. https://doi.org/10.1007/s12016-015-8502-y.
Prieto J, Banales JM, Medina JF. Primary biliary cholangitis: pathogenic mechanisms. Curr Opin Gastroenterol. 2021;37(2):91-98. https://doi.org/10.1097/MOG.0000000000000703.
Houri I, Hirschfield GM. Primary biliary cholangitis. Clin Liver Dis. 2024;28(1):79-92. https://doi.org/10.1016/j.cld.2023.06.006.
Lin CI, Wang YW, Liu CY, Chen HW, Liang PH, Chuang YH. Regulatory T cells in inflamed liver are dysfunctional in murine primary biliary cholangitis. Clin Exp Immunol. 2024;215(3):225-239. https://doi.org/10.1093/cei/uxad117.
Kawata K, Tsuda M, Yang GX, Zhang W, Tanaka H, Tsuneyama K, Leung P, He XS, Knechtle S, Ansari AA, Coppel RL, Gershwin ME. Identification of potential cytokine pathways for therapeutic ıntervention in murine primary biliary cirrhosis. PLoS One. 2013;8(9):e74225. https://doi.org/10.1371/journal.pone.0074225.
Ellinghaus D. How genetic risk contributes to autoimmune liver disease. Semin Immunopathol. 2022;44(4):397–410. https://doi.org/10.1007/s00281-022-00950-8.
Asuri S, McIntosh S, Taylor V, Rokeby A, Kelly J, Shumansky K, Field LL, Yoshida EM, Arbour L. Primary biliary Cholangitis in British Columbia first nations: Clinical features and discovery of novel genetic susceptibility loci. Liver Int. 2018;38(5):940–948. https://doi.org/10.1111/liv.13686.
Chen J, Lyu Y, Huang W, Li Z, Li Y, Yu S, Zeng R, Deng Y, Liang Z, Wang J, Leung FW, Huang J, Sha W, Chen H. Multi-omics analysis reveals potential therapeutic targets and genetic mechanisms in primary biliary cholangitis [Preprint]. Research Square. 2025 [cited 2025 Feb 1]. https://doi.org/10.21203/rs.3.rs-7186861/v1
Yang YC, Ma X, Zhou C, Xu N, Ding D, Ma ZZ, Zhou L, Cui PY. Functional investigation and two-sample Mendelian randomization study of primary biliary cholangitis hub genes. World J Clin Cases. 2024;12(30):6391-6406. https://doi.org/10.12998/wjcc.v12.i30.6391.
Fiorucci S, Urbani G, Di Giorgio C, Biagioli M, Distrutti E. Current landscape and evolving therapies for primary biliary cholangitis. cells. 2024;13(18):1580. https://doi.org/10.3390/cells13181580.
Ueno K, Aiba Y, Hitomi Y, Shimoda S, Nakamura H, Gervais O, Kawai Y, Kawashima M, Nishida N, Kohn SS, Kojima K, Katsushima S, Naganuma A, Sugi K, Komatsu T, Mannami T, Matsushita K, Yoshizawa K, Makita F, Nikami T, Nishimura H, Kouno H, Kouno H, Ohta H, Komura T, Tsuruta S, Yamauchi K, Kobata T, Kitasato A, Kuroki T, Abiru S, Nagaoka S, Komori A, Yatsuhashi H, Migita K, Ohira H, Tanaka A, Takikawa H, Nagasaki M, Tokunaga K, Nakamura M; PBC‐GWAS Consortium in Japan. Integrated GWAS and mRNA microarray analysis identified IFNG and CD40L as the central upstream regulators in primary biliary cholangitis Hepatol Commun. 2020;4(5):724-738. https://doi.org/10.1002/hep4.1497.
Mitchell NE, Chan SY, Jerez Diaz D, Ansari N, Lee J, Twohig P. Evolving therapeutic landscape of primary biliary cholangitis: A review. World J Hepatol. 2025;17(7):107223. https://doi.org/10.4254/wjh.v17.i7.107223
Jhaveri M, Kowdley K. New developments in the treatment of primary biliary cholangitis - role of obeticholic acid. Ther Clin Risk Manag. 2017;13:1053–1060. https://doi.org/10.2147/TCRM.S113052.
Floreani A, Gabbia D, De Martin S. Obeticholic acid for primary biliary cholangitis. Biomedicines. 2022;10(10):2464. https://doi.org/10.3390/biomedicines10102464.
Floreani A, Gabbia D, De Martin S. Reviewing novel findings and advances in diagnoses and treatment of primary biliary cholangitis. Expert Rev Gastroenterol Hepatol. 2025;19(8):891-902. https://doi.org/10.1080/17474124.2025.2537192.
Iljinsky IM, Tsirulnikova OM. Primary biliary cholangitis. Russ J Transplantol Artif Organs. 2021;23(1):162-170. https://doi.org/10.15825/1995-1191-2021-1-162-170.
Fiorucci S, Urbani G, Distrutti E, Biagioli M. Obeticholic acid and other Farnesoid-X-Receptor (FXR) agonists in the treatment of liver disorders. Pharmaceuticals (Basel). 2025;18(9):1424. https://doi.org/10.3390/ph18091424.
Floreani A, Sun Y, Zou ZS, Li B, Cazzagon N, Bowlus CL, Gershwin ME. Proposed therapies in primary biliary cholangitis. Expert Rev Gastroenterol Hepatol. 2016;10(3):371–382. https://doi.org/10.1586/17474124.2016.1121810.
Warsop Z, Anand N, Al Maliki H, De Souza S, Kamyab A, Al Hadad A, Alrubaiy L. Up-to-date snapshot of current and emerging medical therapies in primary biliary cholangitis. J Pers Med. 2024;14(12):1133. https://doi.org/10.3390/jpm14121133.
Arba Bernal R, Ferrigno B, Medina Morales E, Castro CM, Goyes D, Trivedi H, Patwardhan VR, Bonder A. Management of Primary Biliary Cholangitis: Current treatment and future perspectives. Turk J Gastroenterol. 2023;34(2):89–100. https://doi.org/10.5152/tjg.2023.22239.
Pierini E, Mazza L, Petti M, Tieri P. Exploring drug repurposing success stories through a network-based approach: ınsights from a case study. In: 2024 IEEE International Conference on Bioinformatics and Biomedicine (BIBM); 2024 Dec 3-6; Lisbon, Portugal. IEEE; 2024. p. 6959-64. https://doi.org/10.1109/BIBM62325.2024.10822355
Seyath S, Arun TS, Sanjith S, Prasobh GR. A Review on Drug Repurposing: A Functional ınstrument for contemporary drug delivery. Int J Pharm Res Appl. 2025;10(4):266–271. https://doi.org/10.35629/4494-1004266271.
Chikodi Ekeomodi C, Ifeanyi Obetta K, Linus Okolocha M, Nnacho S, Oluwaseun Isijola M, IfedibaluChukwu Ejiofor I. Computational approaches in drug repurposing. In: Drug Repurposing-advances, scopes and opportunities in drug discovery. IntechOpen; 2023. https://doi.org/10.5772/intechopen.110638.
Hong D, Kesselheim A. Strategies to advance drug repurposing for rare diseases [Preprint].DrugArXiv.2025[cited2025Feb1].https://doi.org/10.58647/DRUGARXIV.PR000027.v1
Naffouj S, Wang J. Current and future opportunities for the management of primary biliary cholangitis. Front Gastroenterol. 2023;2:1241901. https://doi.org/10.3389/fgstr.2023.1241901
Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, Ronzano F, Centeno E, Sanz F, Furlong LI. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2019. https://doi.org/10.1093/nar/gkz1021.
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, Bork P, Jensen LJ, von Mering C. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638–D646. https://doi.org/10.1093/nar/gkac1000.
Ono K, Fong D, Gao C, Churas C, Pillich R, Lenkiewicz J, Pratt D, Pico AR, Hanspers K, Xin Y, Morris J, Kucera M, Franz M, Lopes C, Bader G, Ideker T, Chen J. Cytoscape Web: bringing network biology to the browser. Nucleic Acids Res. 2025;53(W1):W203–W212. https://doi.org/10.1093/nar/gkaf365.
Yoo M, Shin J, Kim J, Ryall KA, Lee K, Lee S, Jeon M, Kang J, Tan AC. DSigDB: drug signatures database for gene set analysis. Bioinformatics.2015;31(18):3069-71. https://doi.org/10.1093/bioinformatics/btv313
Liu T, Hwang L, Burley SK, Nitsche CI, Southan C, Walters WP, Gilson MK. BindingDB in 2024: a FAIR knowledgebase of protein-small molecule binding data. Nucleic Acids Res. 2025;53(D1):D1633–D1644. https://doi.org/10.1093/nar/gkae1075.
Bugnon M, Röhrig UF, Goullieux M, Perez MAS, Daina A, Michielin O, Zoete V. SwissDock 2024: major enhancements for small-molecule docking with Attracting Cavities and AutoDock Vina. Nucleic Acids Res. 2024;52(W1):W324–W332. https://doi.org/10.1093/nar/gkae300.
Röhrig UF, Goullieux M, Bugnon M, Zoete V. Attracting Cavities 2.0: Improving the Flexibility and Robustness for Small-Molecule Docking. J Chem Inf Model. 2023;63(12):3925-3940. https://doi.org/10.1021/acs.jcim.3c00054.
Xu C, Rafique A, Potocky T, Paccaly A, Nolain P, Lu Q, Iglesias-Rodriguez M, St John G, Nivens MC, Kanamaluru V, Fairhurst J, Ishii T, Maldonado R, Choy E, Emery P. Differential binding of Sarilumab and Tocilizumab to IL-6Rα and effects of receptor occupancy on clinical parameters. J Clin Pharmacol. 2021;61(5):714-724. https://doi.org/10.1002/jcph.1795.
Rafique A, Martin J, Blome M, Huang T, Ouyang A, Papadopoulos N. Evaluation of the binding kinetics and functional bioassay activity of sarilumab and tocilizumab to the human IL-6 receptor alpha. Ann Rheum Dis. 2013;72:A797. https://doi.org/10.1136/annrheumdis-2013-eular.2360.
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