The pivotal role of NF-κB in polymyxin B toxicity: insights from integrated network toxicology and experimental assays.

Abstract

Polymyxin B remains a first-line therapeutic option against Gram-negative bacterial infections; however, its clinical utility is substantially limited by dose-limiting toxicity, the mechanisms of which remain incompletely elucidated. Within a network toxicology framework, this study systematically investigated the potential toxic characteristics and underlying molecular mechanisms of Polymyxin B, with a specific focus on three key adverse effects: acute kidney injury, neurotoxicity, and skin pigmentation. Potential targets associated with Polymyxin B exposure and these toxicities were initially identified through integrated data mining of the SuperPred, SEA, GeneCards, and OMIM databases. A protein-protein interaction (PPI) network was subsequently constructed and analyzed using the STRING database and Cytoscape software. Functional enrichment analyses, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, were performed using Metascape. Furthermore, a compound-target-pathway network and Sankey diagram were generated to identify major active components, followed by molecular docking between these components and proteins encoded by the key targets. Molecular docking and molecular dynamics simulations confirmed strong binding affinities between Polymyxin B and core target proteins, namely STAT3, NF-κB, PRKACA, and HIF1A. Notably, both PMB1 and PMB2 exhibited high binding affinity for NF-κB. Consistent with these findings, in vivo studies in mice demonstrated that Polymyxin B treatment significantly enhanced the activation of the NF-κB pathway in renal tissues. Conversely, co-administration of the NF-κB pathway inhibitors PDTC and JSH-23 markedly attenuated Polymyxin B-induced nephrotoxicity. In conclusion, these experimental results indicate that hyperactivation of NF-κB is a critical mechanism underlying Polymyxin B-induced renal toxicity.