Fedratinib in chronic kidney disease: antifibrotic potential and renal safety signals from integrated network toxicology and pharmacovigilance.

Chronic kidney disease (CKD), a major global health challenge driven by renal fibrosis, lacks effective antifibrotic therapies. Fedratinib, a JAK2 inhibitor for myelofibrosis, shows kinase-modulating potential but uncharacterized utility and safety in CKD. Computational toxicity prediction utilized ProTox3.0 and ADMETlab2.0. Fedratinib-CKD targets were identified via combinatorial screening across databases (ChEMBL, STITCH, SwissTargetPrediction, GeneCards, OMIM, TTD). Core hubs were determined through protein-protein interaction network (STRING) and topological analysis (Cytoscape). Hierarchical docking validated binding (CB-Dock2). Post-marketing safety data (2019-2025) from FDA Adverse Event Reporting System (FAERS) was analyzed using disproportionality methods, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS). Computational profiling predicted severe respiratory, hepatic and cardiac toxicity but negligible nephrotoxicity. Network analysis identified 281 shared targets, with SRC, AKT1, EGFR and JAK2 as core hubs. Pathway enrichment revealed profound suppression of PI3K-Akt and MAPK signaling. Docking confirmed high-affinity binding. FAERS analysis of 1,268 reports identified significant renal and urinary disorders (ROR = 1.71) and extreme vitamin B1 deficiency (ROR = 1262.53), contradicting computational predictions. Fedratinib exhibits therapeutic duality: inhibition of SRC and JAK2 attenuates fibrosis by inhibiting JAK-STAT/TGFβ/Smad3 pathways, while off-target binding to AKT1/EGFR drives renal injury and vitamin B1 depletion-related toxicity with black-box encephalopathy warning. Evidence suggests for CKD patients with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 or age ≥70 years, a 50% dose reduction (200 mg/day) with renal function and thiamin monitoring (<30 nmol/L) may optimize risk-benefit profile.