Fluconazole-induced liver injury in patients with pulmonary cryptococcosis: a comprehensive study integrating clinical cohort analysis, network toxicology, molecular docking, and transcriptomics
Year: 2026
Type: article
Study design: Observational Study
Abstract: ABSTRACT Fluconazole is key for pulmonary cryptococcosis (PC), but its hepatotoxicity (HT) risk is unclear. This study characterized fluconazole-induced liver injury in HIV-negative PC patients and explored its mechanism. We integrated clinical cohort analysis ( n = 123), network toxicology, molecular docking, and transcriptomics. HT incidence was 23.6%, predominantly cholestatic (55.2%). Immunocompromised status independently increased HT risk (aRR = 2.67, P = 0.004). Baseline ALT >16.5 U/L was the best predictor (AUC = 0.69) among liver enzymes, which showed modest discriminatory value. A model combining liver enzymes, immune status, and comedications achieved superior prediction (AUC = 0.76). Mechanistically, AKT1, ERBB2, and KDR were identified as potential core targets. Transcriptomics confirmed their significant downregulation in general cholestasis models, and molecular docking demonstrated favorable affinity binding with fluconazole (strongest for KDR: −6.5 kcal/mol). In conclusion, baseline liver enzymes and immune status are critical risk factors for fluconazole-induced HT, and fluconazole-induced cholestatic injury may involve the dysregulation of signaling pathways centered on AKT1, ERBB2, and KDR, suggesting potential targets for monitoring.
DOI: 10.1128/aac.01976-25
Authors: Yiding Xu, Lei Chen, Jie Liu, Qin Wang, Xiaodan Zhu, Minghui Wang, Jianghong Li, Lin Shi, Hongni Jiang
Institutions: Fudan University, Zhongshan Hospital
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7155011823