Baricitinib in chronic kidney disease: an exploratory analysis integrating network toxicology, molecular docking and...

Chronic kidney disease (CKD) presents a major global health challenge due to ineffective therapies against progressive renal fibrosis. Baricitinib, a selective JAK1/JAK2 inhibitor, has anti-inflammatory and anti-fibrotic potential, yet its mechanistic basis and safety implications in CKD require further exploration.

An integrated strategy was employed, combining network toxicology across multiple databases, protein-protein interaction network analysis and molecular docking. Real-world safety was evaluated by analyzing adverse event (AE) reports from FDA Adverse Event Reporting System (FAERS) (2018-2024), capturing safety data across all approved indications for baricitinib by calculating reporting odds ratios (RORs) and proportional reporting ratios (PRRs).

Predictive toxicology indicated potential respiratory and acute toxicity risks. Network analysis identified 229 shared targets; core hubs (AKT1, SRC, STAT3, EGFR, ESR1) showed high-affinity docking, suggesting potentially stronger theoretical binding affinity than JAK1. Pathway enrichment suggested potential suppression of JAK-STAT/MAPK and TGF-β/Smad3 pathways. FAERS analysis of 6,006 reports from its broader clinical use showed significantly elevated RORs for infections and thromboembolic events, alongside the absence of a disproportionate signal for renal AEs. This finding aligns with the mechanistic profile derived from intersecting baricitinib's predicted targets with CKD-related genes, highlighting the need to systematically evaluate renal safety in prospective CKD trials.

Baricitinib has computational and mechanistic potential to modulate key pathways in CKD. Pharmacovigilance data confirm risks of infection and thrombosis but show no disproportionate renal safety signal. These exploratory findings generate a testable hypothesis for its use in CKD, underscoring the necessity of prospective, renal-function-stratified trials.