Fluconazole-induced liver injury in patients with pulmonary cryptococcosis: a comprehensive study integrating clinical cohort analysis, network toxicology, molecular docking, and transcriptomics

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.