An integrated multiscale computational study of nephrotoxicity mechanism of citrinin and its metabolites (CIMs)：density functional theory, network toxicology, and molecular dynamics simulation.

Citrinin is a common mycotoxin found in food and poses risks to both human and animal health. While extensive research has been conducted on the nephrotoxicity of citrinin itself, the nephrotoxicity of its metabolites remains unclear. Therefore, this study investigated the nephrotoxic mechanism of citrinin and its metabolites (CIMs) using density functional theory, network toxicology, and computer simulations. Our findings revealed that CIMs also have potential toxicity, such as nephrotoxicity. Density functional theory explained the structural basis of the toxicity of CIMs. A total of 255 targets related to nephrotoxicity induced by CIMs were predicted by network toxicology. Notably, the enrichment results indicated the importance of multiple forms of programmed cell death in CIMs-induced nephrotoxicity. In addition, four key targets (TP53, MAPK1, MAPK3, and HSP90AA1) were identified, with molecular dynamics simulations validating stable binding between the four targets and CIMs. Van der Waals forces were the main driving force for stabilizing complexes formed between CIMs and the four targets through the binding free energy and independent gradient model analysis. Our research provides the theoretical basis and new insights for an in-depth study of the nephrotoxicity mechanism of CIMs and offers a new paradigm/approach for investigating the toxicity mechanism of other mycotoxins in the future.