{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:00:43Z","timestamp":1790913643879,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Investigate the high risk factors contributed to voriconazole-induced liver injury and develop a predictive nomogram for voriconazole-induced liver injury risk, thereby optimizing the clinical medication safety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This observational study retrospectively analyzed the electronic health records of hospitalized patients who received voriconazole treatment or prophylaxis at a tertiary hospital. Patients who met the inclusion and exclusion criteria were enrolled between June 2020 and June 2024, and their general biological data were collected. The diagnosis and severity grading of voriconazole-associated liver injury were determined according to the diagnostic and treatment guidelines for drug-induced liver injury. Patients were categorized into liver injury and non-injury groups based on the results of post-treatment liver function tests. Associations between baseline characteristics and liver injury were analyzed using non-parametric and chi-squared tests. To avoid omitting potentially significant factors, variables demonstrating\n                      <jats:italic>P<\/jats:italic>\n                      \u2264 0.1 in univariate screening and retained through least absolute shrinkage and selection operator (LASSO) regression underwent multivariate logistic regression to identify independent predictors. The nomogram was developed and internally validated through receiver operating characteristic (ROC) analysis, calibration curves, and decision curve analysis (DCA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among the 1,964 patients screened, 1,196 were excluded, leaving 768 patients included in the statistical analysis. Liver injury occurred in 95 patients, resulting in an incidence rate of 12.4%. Multivariable logistic regression analysis demonstrated that total cholesterol (TC) (OR = 1.893,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01), concomitant use of glucocorticoids (OR = 1.861,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.041), ezetimibe (OR = 7.453,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.047), and caspofungin (OR = 2.485,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.032). Patients with TC levels exceeding 4.485\u00a0mmol\/L exhibited a significantly elevated risk of liver injury. ROC analysis revealed an area under the curve (AUC) of 0.728 (95% CI: 0.66\u20130.797), with a sensitivity of 0.661 and specificity of 0.722. Internal validation indicated good discrimination and calibration, with predicted probabilities closely aligned with actual outcomes. The decision curve analysis suggested a substantial net clinical benefit. These findings were subsequently validated in a test cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Concomitant use of ezetimibe, caspofungin, glucocorticoids, and TC levels exceeding 4.485\u00a0mmol\/L are independent risk factors for voriconazole-induced liver injury. The developed nomogram model offers clinically meaningful predictions for drug-induced liver injury risk, facilitating the optimization of voriconazole therapy safety.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1688711","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T06:36:18Z","timestamp":1767594978000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Voriconazole-associated liver injury: clinical risk factor identification and predictive nomogram construction"],"prefix":"10.3389","volume":"16","author":[{"given":"Dongge","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]},{"name":"School of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyi","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]},{"name":"School of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]},{"name":"School of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijian","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Seventh Affiliated Hospital, Sun Yat-sen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1038\/clpt.2011.58","article-title":"Case definition and phenotype standardization in drug-induced liver injury","volume":"89","author":"Aithal","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/s13318-019-00603-6","article-title":"Effect of gender and age on voriconazole trough concentrations in Italian adult patients","volume":"45","author":"Allegra","year":"2020","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41572-019-0105-0","article-title":"Drug-induced liver injury","volume":"5","author":"Andrade","year":"2019","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e0148868","DOI":"10.1371\/journal.pone.0148868","article-title":"Carvedilol improves inflammatory response, oxidative stress and fibrosis in the alcohol-induced liver injury in rats by regulating kuppfer cells and hepatic stellate cells","volume":"11","author":"Ara\u00fajo","year":"2016","journal-title":"PLoS One"},{"key":"B5","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1093\/cid\/ciae203","article-title":"Breakthrough invasive fungal infections in patients with high-risk hematological disorders receiving voriconazole and posaconazole prophylaxis: a systematic review","volume":"79","author":"Boutin","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1097\/FTD.0000000000000561","article-title":"Individualized medication of voriconazole: a practice guideline of the division of therapeutic drug monitoring, Chinese pharmacological society","volume":"40","author":"Chen","year":"2018","journal-title":"Ther. Drug Monit."},{"key":"B7","doi-asserted-by":"publisher","first-page":"106506","DOI":"10.1016\/j.ejps.2023.106506","article-title":"Prediction of plasma trough concentration of voriconazole in adult patients using machine learning","volume":"188","author":"Cheng","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1111\/liv.14349","article-title":"EASL clinical practice guidelines for the management of occupational liver diseases","volume":"40","author":"Colombo","year":"2020","journal-title":"Liver Int."},{"key":"B9","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1097\/MOL.0b013e3283613a55","article-title":"Ezetimibe and bile acid sequestrants: impact on lipoprotein metabolism and beyond","volume":"24","author":"Couture","year":"2013","journal-title":"Curr. Opin. Lipidol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/ijms17010014","article-title":"RUCAM in drug and herb induced liver injury: the update","volume":"17","author":"Danan","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1093\/jac\/dkl108","article-title":"Incidence of voriconazole hepatotoxicity during intravenous and oral treatment for invasive fungal infections","volume":"57","author":"Den Hollander","year":"2006","journal-title":"J. Antimicrob. Chemother."},{"key":"B12","doi-asserted-by":"publisher","first-page":"106614","DOI":"10.1016\/j.ijantimicag.2022.106614","article-title":"Comparative efficacy and safety of systemic antifungal agents for candidemia: a systematic review with network meta-analysis and multicriteria acceptability analyses","volume":"60","author":"Domingos","year":"2022","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B13","doi-asserted-by":"publisher","first-page":"110693","DOI":"10.1016\/j.cbi.2023.110693","article-title":"Metabolic characteristics of voriconazole - induced liver injury in rats","volume":"383","author":"Du","year":"2023","journal-title":"Chem. Biol. Interact."},{"key":"B14","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.ad.2019.05.009","article-title":"Using the common terminology criteria for adverse events (CTCAE - Version 5.0) to evaluate the severity of adverse events of anticancer therapies","volume":"112","author":"Freites-Martinez","year":"2021","journal-title":"Actas Dermosifiliogr. Engl. Ed."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1111\/myc.13639","article-title":"Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients","volume":"66","author":"Hanai","year":"2023","journal-title":"Mycoses"},{"key":"B16","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1089\/ars.2011.4269","article-title":"Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1","volume":"19","author":"Hern\u00e1ndez-Alvarez","year":"2013","journal-title":"Antioxid. Redox Signal"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e12886","DOI":"10.1111\/tid.12886","article-title":"Voriconazole concentration is inversely correlated with corticosteroid usage in immunocompromised patients","volume":"20","author":"Imataki","year":"2018","journal-title":"Transpl. Infect. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1194\/jlr.M072454","article-title":"Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH","volume":"58","author":"Ioannou","year":"2017","journal-title":"J. Lipid Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"666296","DOI":"10.3389\/fphar.2021.666296","article-title":"Interactive effects of glucocorticoids and cytochrome P450 polymorphisms on the plasma trough concentrations of voriconazole","volume":"12","author":"Jia","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1093\/jac\/dkw045","article-title":"Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis","volume":"71","author":"Jin","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"B21","article-title":"Clinical and research information on drug-induced liver injury","year":"2012"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.3390\/molecules24101982","article-title":"Dexamethasone-induced mitochondrial dysfunction and insulin resistance-study in 3T3-L1 adipocytes and mitochondria isolated from mouse liver","volume":"24","author":"Luan","year":"2019","journal-title":"Molecules"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1109\/EMBC40787.2023.10340343","article-title":"The investigation and prediction of voriconazole-associated hepatotoxicity under therapeutic drug monitoring","volume":"2023","author":"Ma","year":"2023","journal-title":"Annu. Int. Conf. IEEE Eng. Med. Biol. Soc."},{"key":"B24","doi-asserted-by":"publisher","first-page":"909","DOI":"10.3390\/antiox9100909","article-title":"Mitochondrial glutathione: recent insights and role in disease","volume":"9","author":"Mar\u00ed","year":"2020","journal-title":"Antioxidants (Basel)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"25776","DOI":"10.1074\/jbc.M116.752311","article-title":"Glucocorticoid receptor \u03b2 induces hepatic steatosis by augmenting inflammation and inhibition of the peroxisome proliferator-activated receptor (PPAR) \u03b1","volume":"291","author":"Marino","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"852","DOI":"10.3390\/ijms24010852","article-title":"Hepatotoxicity of drugs used in multiple sclerosis, diagnostic challenge, and the role of HLA genotype susceptibility","volume":"24","author":"Meunier","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/cid\/ciw326","article-title":"Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America","volume":"63","author":"Patterson","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1177\/1078155218786028","article-title":"Evaluating a voriconazole dose modification guideline to optimize dosing in patients with hematologic malignancies","volume":"25","author":"Perreault","year":"2019","journal-title":"J. Oncol. Pharm. Pract."},{"key":"B29","doi-asserted-by":"publisher","first-page":"148","DOI":"10.4103\/picr.PICR_87_17","article-title":"Common pitfalls in statistical analysis: logistic regression","volume":"8","author":"Ranganathan","year":"2017","journal-title":"Perspect. Clin. Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1097\/MEG.0b013e3282f1752d","article-title":"Severe jaundice following treatment with ezetimibe","volume":"20","author":"Ritchie","year":"2008","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1080\/03602532.2019.1632888","article-title":"Novel insights into the complex pharmacokinetics of voriconazole: a review of its metabolism","volume":"51","author":"Schulz","year":"2019","journal-title":"Drug Metab. Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1592\/phco.27.7.970","article-title":"Institutional experience with voriconazole compared with liposomal amphotericin B as empiric therapy for febrile neutropenia","volume":"27","author":"Shehab","year":"2007","journal-title":"Pharmacotherapy"},{"key":"B33","doi-asserted-by":"publisher","first-page":"20420986221127503","DOI":"10.1177\/20420986221127503","article-title":"Therapeutic drug monitoring and safety evaluation of voriconazole in the treatment of pulmonary fungal diseases","volume":"13","author":"Shen","year":"2022","journal-title":"Ther. Adv. Drug Saf."},{"key":"B34","doi-asserted-by":"publisher","first-page":"71","DOI":"10.2133\/dmpk.18.71","article-title":"Bioinformatics research on inter-racial difference in drug metabolism II. Analysis on relationship between enzyme activities of CYP2D6 and CYP2C19 and their relevant genotypes","volume":"18","author":"Shimizu","year":"2003","journal-title":"Drug Metab. Pharmacokinet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1016\/j.cmet.2021.09.001","article-title":"Cholesterol-induced toxicity: an integrated view of the role of cholesterol in multiple diseases","volume":"33","author":"Song","year":"2021","journal-title":"Cell Metab."},{"key":"B36","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.drudis.2008.11.009","article-title":"The future of drug safety testing: expanding the view and narrowing the focus","volume":"14","author":"Stevens","year":"2009","journal-title":"Drug Discov. Today"},{"key":"B37","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13054-014-0722-7","article-title":"Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes","volume":"19","author":"Taccone","year":"2015","journal-title":"Crit. Care"},{"key":"B38","doi-asserted-by":"publisher","first-page":"101976","DOI":"10.1016\/j.toxrep.2025.101976","article-title":"Insights into medication-induced liver injury: understanding and management strategies","volume":"14","author":"Tiwari","year":"2025","journal-title":"Toxicol. Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"106692","DOI":"10.1016\/j.ijantimicag.2022.106692","article-title":"Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: a nationwide multi-centre retrospective study","volume":"60","author":"Wang","year":"2022","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B40","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1111\/cts.12629","article-title":"The DILI-Sim initiative: insights into hepatotoxicity mechanisms and biomarker interpretation","volume":"12","author":"Watkins","year":"2019","journal-title":"Clin. Transl. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.3389\/fimmu.2018.01920","article-title":"Repositioning of the \u03b2-Blocker carvedilol as a novel autophagy inducer that inhibits the NLRP3 inflammasome","volume":"9","author":"Wong","year":"2018","journal-title":"Front. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.2147\/DDDT.S210797","article-title":"Carvedilol attenuates carbon tetrachloride-induced liver fibrosis and hepatic sinusoidal capillarization in mice","volume":"13","author":"Wu","year":"2019","journal-title":"Drug Des. Devel Ther."},{"key":"B43","doi-asserted-by":"publisher","first-page":"115157","DOI":"10.1016\/j.taap.2020.115157","article-title":"Metabolomics analysis of plasma reveals voriconazole-induced hepatotoxicity is associated with oxidative stress","volume":"403","author":"Wu","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"483","DOI":"10.2147\/IDR.S301198","article-title":"Hyperlipidemia caused by voriconazole: a case report","volume":"14","author":"Wu","year":"2021","journal-title":"Infect. Drug Resist"},{"key":"B45","doi-asserted-by":"publisher","first-page":"7475","DOI":"10.2147\/IDR.S391022","article-title":"Central nervous system toxicity of voriconazole: risk factors and threshold - a retrospective cohort study","volume":"15","author":"Yang","year":"2022","journal-title":"Infect. Drug Resist"},{"key":"B46","doi-asserted-by":"publisher","first-page":"780496","DOI":"10.3389\/fphar.2022.780496","article-title":"The NLRP3 inflammasome in non-alcoholic fatty liver disease and steatohepatitis: therapeutic targets and treatment","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"891336","DOI":"10.3389\/fphar.2022.891336","article-title":"Antifungal drugs and drug-induced liver injury: a real-world study leveraging the FDA adverse event reporting system database","volume":"13","author":"Zhou","year":"2022","journal-title":"Front. Pharmacol."}],"updated-by":[{"DOI":"10.3389\/fphar.2026.1834410","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000}}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1688711\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T09:38:38Z","timestamp":1774604318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1688711\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,5]]},"references-count":47,"alternative-id":["10.3389\/fphar.2025.1688711"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1688711","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,5]]},"article-number":"1688711"}}