Nephrotoxicity induced by the chemotherapeutic drug arsenic trioxide (ATO) is often overlooked, and the underlying mechanisms remain poorly understood. Based on network pharmacology and experimental validation, this study investigates the protection of 6-gingerol (6G) against ATO-induced nephrotoxicity and the potential mechanisms.We screened and collected 6G and disease-related targets and then imported the interaction targets into a String database to construct protein-protein interaction (PPI) networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Mice were injected intraperitoneally with ATO (5 mg/kg) for seven days to induce nephrotoxicity, and then the histological morphology of the kidneys, biochemical indices of serum and tissues, and associated protein expressions were observed.The network pharmacology results revealed that the effects of 6G against nephrotoxicity are closely related to apoptosis, and the MAPKs pathway was screened for validation. In animal experiments, 6G improved the histopathological morphology of the kidneys, reduced the levels of renal function markers, enhanced antioxidant activity, and decreased the levels of inflammation. Furthermore, 6G reduced apoptotic cells in kidney tissues, decreased the levels of Bax and c-Caspase-3, and increased the level of Bcl-2. The results of immunohistochemistry and western blotting revealed that 6G significantly inhibited the expressions of p-p38, p-ERK, and p-JNK.The results comprehensively demonstrate the protective effects of 6G against ATO-induced nephrotoxicity. The effects are related to anti-oxidant, anti-inflammatory, and anti-apoptotic properties, possibly through inhibition of the MAPKs pathway.Copyright © 2022 Elsevier B.V. All rights reserved.