{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:50:59Z","timestamp":1790884259558,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T00:00:00Z","timestamp":1709769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Maintenance Project of the Center for Big Data Analytics and Statistics","award":["CLRPG3N0011"],"award-info":[{"award-number":["CLRPG3N0011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatitis B virus (HBV)-related liver cirrhosis (HBV-LC) presents a substantial mortality and hepatocellular carcinoma (HCC) risk. While antiviral therapy (AVT) is the standard, complete HBV clearance remains elusive and may not reduce the risk of death in patients with decompensated cirrhosis. Silymarin, a centuries-old herbal remedy, has shown promise against HBV infection and as an antifibrosis therapy. This study explores the potential of silymarin combined with AVT to reduce mortality and HCC incidence in patients with HBV-LC. This research, spanning from 2001 to 2019, entailed a multi-institutional retrospective cohort study which included 8447 HBV-LC patients all undergoing AVT. After applying inclusion and exclusion criteria, the study comprised two cohorts: a case cohort receiving silymarin alongside AVT for at least 30 days, and a control cohort on AVT alone. Propensity score matching, based on baseline parameters including HBV-DNA levels, comorbidity, and an important LC medication, namely, non-selective \u03b2-blockers, was employed to ensure balanced groups, resulting in 319 patients in each cohort for subsequent analyses. Overall mortality was the primary outcome, with HCC occurrence as a secondary outcome. Among 319 patients in both cohorts, the case cohort exhibited significant improvements in the international normalized ratio (INR), model for end-stage liver disease (MELD) score and the Charlson comorbidity index (CCI) one year after the index date. A competing risk survival analysis demonstrated superior one-year and two-year mortality outcomes in the case cohort. However, no significant impact on one-year and two-year HCC occurrence was observed in either cohort. The combination of silymarin and AVT in HBV-LC patients demonstrated a synergistic effect, leading to decreased overall mortality and an improved comorbidity index. While the incidence of HCC remained unchanged, our results suggested promising potential for further clinical trials investigating the synergistic role of silymarin in the treatment of HBV-LC.<\/jats:p>","DOI":"10.3390\/ijms25063088","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T04:19:02Z","timestamp":1709785142000},"page":"3088","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Silymarin Synergizes with Antiviral Therapy in Hepatitis B Virus-Related Liver Cirrhosis: A Propensity Score Matching Multi-Institutional Study"],"prefix":"10.3390","volume":"25","author":[{"given":"Chien-Hao","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan"},{"name":"School of Medicine, College of Medicine, Chang Gung University, Taoyuan City 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9918-4369","authenticated-orcid":false,"given":"Victor Chien-Chia","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, Chang Gung University, Taoyuan City 33305, Taiwan"},{"name":"Department of Cardiology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Li","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, Chang Gung University, Taoyuan City 33305, Taiwan"},{"name":"Department of Cardiology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Ling","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Big Data Analytics and Statistics, Department of Medical Research and Development, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-7238","authenticated-orcid":false,"given":"Yu-Tung","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Big Data Analytics and Statistics, Department of Medical Research and Development, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang-Hung","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, Chang Gung University, Taoyuan City 33305, Taiwan"},{"name":"Department of Cardiology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan"},{"name":"Center for Big Data Analytics and Statistics, Department of Medical Research and Development, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/S0140-6736(09)60207-5","article-title":"Hepatitis B virus infection","volume":"373","author":"Liaw","year":"2009","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kaur, S.P., Talat, A., Karimi-Sari, H., Grees, A., Chen, H.W., Lau, D.T.Y., and Catana, A.M. (2022). Hepatocellular Carcinoma in Hepatitis B Virus-Infected Patients and the Role of Hepatitis B Surface Antigen (HBsAg). J. Clin. Med., 11.","DOI":"10.3390\/jcm11041126"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S2468-1253(18)30056-6","article-title":"Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: A modelling study","volume":"3","author":"Gamkrelidze","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Chien, R.N., and Liaw, Y.F. (2022). Current Trend in Antiviral Therapy for Chronic Hepatitis B. Viruses, 14.","DOI":"10.3390\/v14020434"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Liu, C.J., and Chen, P.J. (2020). Elimination of Hepatitis B in Highly Endemic Settings: Lessons Learned in Taiwan and Challenges Ahead. Viruses, 12.","DOI":"10.3390\/v12080815"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/S0140-6736(08)60383-9","article-title":"Liver cirrhosis","volume":"371","author":"Schuppan","year":"2008","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1056\/NEJMoa033364","article-title":"Lamivudine for patients with chronic hepatitis B and advanced liver disease","volume":"351","author":"Liaw","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1002\/hep.26301","article-title":"Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis","volume":"58","author":"Wong","year":"2013","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.jhep.2012.02.033","article-title":"Hepatitis B virus-related decompensated liver cirrhosis: Benefits of antiviral therapy","volume":"57","author":"Peng","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/S0140-6736(22)01468-4","article-title":"Hepatitis B","volume":"401","author":"Jeng","year":"2023","journal-title":"Lancet"},{"key":"ref_11","first-page":"20","article-title":"Inhibitory effect of silibinin on hepatitis B virus entry","volume":"14","author":"Umetsu","year":"2018","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/hep.29406","article-title":"Recombinant covalently closed circular DNA of hepatitis B virus induces long-term viral persistence with chronic hepatitis in a mouse model","volume":"67","author":"Li","year":"2018","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1136\/gutjnl-2015-309809","article-title":"HBV cccDNA: Viral persistence reservoir and key obstacle for a cure of chronic hepatitis B","volume":"64","author":"Nassal","year":"2015","journal-title":"Gut."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1016\/j.cgh.2020.08.064","article-title":"Hepatic Decompensation in Cirrhotic Patients Receiving Antiviral Therapy for Chronic Hepatitis B","volume":"19","author":"Lee","year":"2021","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Huang, C.H., Tsai, M.H., and Lin, C.Y. (2024). Identifying the pivotal role of non-acute decompensation as a precursor to acute decompensation in cirrhosis. J. Hepatol.","DOI":"10.1016\/j.jhep.2024.02.002"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tonon, M., D\u2019Ambrosio, R., Calvino, V., Tosetti, G., Barone, A., Incicco, S., Gambino, C., Gagliardi, R., Borghi, M., and Zeni, N. (2023). A new clinical and prognostic characterization of the patterns of decompensation of cirrhosis. J. Hepatol.","DOI":"10.1016\/j.jhep.2023.12.005"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1002\/hep.27723","article-title":"Long-term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus-related cirrhosis","volume":"61","author":"Jang","year":"2015","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1053\/gast.2002.35352","article-title":"Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy","volume":"123","author":"Fontana","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/jgh.16132","article-title":"The clinical effect of antiviral therapy in patients with hepatitis B virus-related decompensated cirrhosis and undetectable DNA","volume":"38","author":"Lee","year":"2023","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1111\/j.1365-2893.2005.00636.x","article-title":"Silymarin treatment of viral hepatitis: A systematic review","volume":"12","author":"Mayer","year":"2005","journal-title":"J. Viral Hepat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1097\/CAD.0000000000000211","article-title":"Silymarin and hepatocellular carcinoma: A systematic, comprehensive, and critical review","volume":"26","author":"Mastron","year":"2015","journal-title":"Anticancer Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41575-020-00372-7","article-title":"Molecular and cellular mechanisms of liver fibrosis and its regression","volume":"18","author":"Kisseleva","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"204","DOI":"10.3390\/antiox4010204","article-title":"Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives","volume":"4","author":"Surai","year":"2015","journal-title":"Antioxidants"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"473","DOI":"10.3892\/ijmm.2012.1029","article-title":"Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: Analysis of isolated hepatic stellate cells","volume":"30","author":"Kim","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"144","DOI":"10.4254\/wjh.v6.i3.144","article-title":"Hepatoprotective effect of silymarin","volume":"6","year":"2014","journal-title":"World J. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/j.jhep.2014.08.033","article-title":"Hepatitis B flares in chronic hepatitis B: Pathogenesis, natural course, and management","volume":"61","author":"Chang","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"k2817","DOI":"10.1136\/bmj.k2817","article-title":"Mortality due to cirrhosis and liver cancer in the United States, 1999\u20132016: Observational study","volume":"362","author":"Tapper","year":"2018","journal-title":"BMJ"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s10096-012-1789-1","article-title":"Meta-analysis: Silymarin and its combination therapy for the treatment of chronic hepatitis B","volume":"32","author":"Wei","year":"2013","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1111\/j.1478-3231.2005.01134.x","article-title":"Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2005 update","volume":"25","author":"Liaw","year":"2005","journal-title":"Liver Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s12072-008-9080-3","article-title":"Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2008 update","volume":"2","author":"Liaw","year":"2008","journal-title":"Hepatol. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s12072-012-9365-4","article-title":"Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2012 update","volume":"6","author":"Liaw","year":"2012","journal-title":"Hepatol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12072-015-9675-4","article-title":"Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update","volume":"10","author":"Sarin","year":"2016","journal-title":"Hepatol. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1055\/s-0041-1729973","article-title":"Erratum to: Finite Antiviral Therapy in Chronic Hepatitis B Patients with Cirrhosis","volume":"41","author":"Jeng","year":"2021","journal-title":"Semin. Liver Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jfma.2018.11.008","article-title":"Taiwan consensus statement on the management of chronic hepatitis B","volume":"118","author":"Chien","year":"2019","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9199190","DOI":"10.1155\/2022\/9199190","article-title":"Effect of Silymarin as an Adjunct Therapy in Combination with Sofosbuvir and Ribavirin in Hepatitis C Patients: A Miniature Clinical Trial","volume":"2022","author":"Ahmed","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/S0002-9343(02)01244-5","article-title":"Milk thistle for the treatment of liver disease: A systematic review and meta-analysis","volume":"113","author":"Jacobs","year":"2002","journal-title":"Am. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1007\/s12325-020-01251-y","article-title":"Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review","volume":"37","author":"Gillessen","year":"2020","journal-title":"Adv. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1053\/j.gastro.2007.02.038","article-title":"Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin","volume":"132","author":"Polyak","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1073\/pnas.0914009107","article-title":"Identification of hepatoprotective flavonolignans from silymarin","volume":"107","author":"Polyak","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","first-page":"4457","article-title":"Anticancer potential of silymarin: From bench to bed side","volume":"26","author":"Agarwal","year":"2006","journal-title":"Anticancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1002\/hep.26179","article-title":"Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection","volume":"57","author":"Polyak","year":"2013","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2174\/092986707779941159","article-title":"Silybin and silymarin--new and emerging applications in medicine","volume":"14","author":"Gazak","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1053\/j.gastro.2009.09.021","article-title":"Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection","volume":"138","author":"Morishima","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1002\/hep.23587","article-title":"Multiple effects of silymarin on the hepatitis C virus lifecycle","volume":"51","author":"Wagoner","year":"2010","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1053\/j.gastro.2009.11.053","article-title":"Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase","volume":"138","author":"Ahnou","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jcv.2010.07.006","article-title":"Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient","volume":"49","author":"Payer","year":"2010","journal-title":"J. Clin. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Federico, A., Dallio, M., and Loguercio, C. (2017). Silymarin\/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules, 22.","DOI":"10.3390\/molecules22020191"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Nam, J.Y., Lee, J.H., Kim, H.Y., Kim, J.E., Lee, D.H., Chang, Y., Cho, H., Yoo, J.J., Lee, M., and Cho, Y.Y. (2017). Oral Medications Enhance Adherence to Surveillance for Hepatocellular Carcinoma and Survival in Chronic Hepatitis B Patients. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0166188"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0168-8278(89)90083-4","article-title":"Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver","volume":"9","author":"Ferenci","year":"1989","journal-title":"J. Hepatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1111\/liv.13253","article-title":"Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients","volume":"36","author":"Su","year":"2016","journal-title":"Liver Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/hep.24109","article-title":"Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure","volume":"53","author":"Garg","year":"2011","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.cld.2007.08.005","article-title":"Long-term outcomes in hepatitis B: The REVEAL-HBV study","volume":"11","author":"Chen","year":"2007","journal-title":"Clin. Liver Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1001\/jama.295.1.65","article-title":"Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level","volume":"295","author":"Chen","year":"2006","journal-title":"JAMA"},{"key":"ref_54","first-page":"1","article-title":"Toxicology and carcinogenesis studies of milk thistle extract (CAS No. 84604-20-6) in F344\/N rats and B6C3F1 mice (Feed Studies)","volume":"565","year":"2011","journal-title":"Natl. Toxicol. Program Tech. Rep. Ser."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1002\/cam4.1998","article-title":"Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment","volume":"8","author":"Tarao","year":"2019","journal-title":"Cancer Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e701","DOI":"10.1016\/S2468-2667(23)00149-4","article-title":"Hepatitis B and C in Europe: An update from the Global Burden of Disease Study 2019","volume":"8","author":"Cortesi","year":"2023","journal-title":"Lancet. Public. Health."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105384","DOI":"10.1016\/j.jff.2022.105384","article-title":"Silymarin in cancer therapy: Mechanisms of action, protective roles in chemotherapy-induced toxicity, and nanoformulations","volume":"100","author":"Wang","year":"2023","journal-title":"J. Funct. Foods"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 signaling pathway: Pivotal roles in inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Fuertes-Agudo, M., Luque-Tevar, M., Cucarella, C., Martin-Sanz, P., and Casado, M. (2023). Advances in Understanding the Role of NRF2 in Liver Pathophysiology and Its Relationship with Hepatic-Specific Cyclooxygenase-2 Expression. Antioxidants, 12.","DOI":"10.3390\/antiox12081491"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10512","DOI":"10.3748\/wjg.v22.i48.10512","article-title":"Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets","volume":"22","author":"Zhang","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1365-2036.2010.04503.x","article-title":"Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial","volume":"33","author":"Freedman","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.bj.2017.08.002","article-title":"Chang Gung Research Database: A multi-institutional database consisting of original medical records","volume":"40","author":"Tsai","year":"2017","journal-title":"Biomed. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1007\/s10620-023-07943-z","article-title":"Prognostic Effects of Liver Fibrosis and Steatosis Determined Using Transient Elastography in Patients with Chronic Hepatitis B or C","volume":"68","author":"Wang","year":"2023","journal-title":"Dig. Dis. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/pds.4713","article-title":"The Chang Gung Research Database-A multi-institutional electronic medical records database for real-world epidemiological studies in Taiwan","volume":"28","author":"Shao","year":"2019","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3892\/mco.2023.2631","article-title":"Optimal dose of silymarin for the management of drug-induced liver injury in oncology","volume":"18","author":"Kohutek","year":"2023","journal-title":"Mol. Clin. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3088\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:10:16Z","timestamp":1760105416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,7]]},"references-count":65,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25063088"],"URL":"https:\/\/doi.org\/10.3390\/ijms25063088","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,7]]}}}