Oxaliplatin (OXA)-induced peripheral neurotoxicity (OIPN) is a high-incidence and dose-dependent adverse reaction during OXA treatment. Its underlying mechanisms remain unclear, and no effective treatment or prevention therapies are currently available. Here, we employed a data independent acquisition (DIA)-based quantitative proteomic strategy to investigate the global proteome alterations in the dorsal root ganglion (DRG) tissues from mice injected with OXA for different periods. We identified 1128 differentially regulated proteins that were divided into six subclusters according to their alteration trends. Interestingly, these proteins were involved in cellular processes such as cell cycle, ribosomal stress, metabolism, and ion transport. In addition, OXA administration induced abundance changes of ion channels and proteins associated with mitochondrial function and reactive oxygen species production. Furthermore, we investigated the effects of diroximel fumarate (DRF), an FDA-approved oral fumarate drug for the treatment of relapsing forms of multiple sclerosis. Our findings showed that DRF could effectively ameliorate symptoms of OIPN and reduce the level of oxidative stress in mice. Taken together, our study systematically mapped the proteome alteration associated with the neural toxicity of OXA, and the findings could be leveraged to better understand the mechanisms of OIPN and to develop more effect treatment therapies. SIGNIFICANCE: Oxaliplatin (OXA)-induced peripheral neurotoxicity (OIPN) is a high-incidence and dose-dependent adverse reaction with unclear mechanism. Here we employed a data independent acquisition (DIA)-based quantitative proteomic strategy to explore the proteome changes in dorsal root ganglion (DRG) tissues from mice treated by OXA. The findings provided novel insights regarding the mechanisms of OIPN. For example, our data showed that OXA induced a broad disturbance in metabolism, particularly in glycolysis and amino acid metabolism. Additionally, we observed abundance changes of many ion channels and proteins associated with mitochondrial function and reactive oxygen species production. Furthermore, this study provided the first evidence for the possibility of repositioning diroximel fumarate (DRF) for treating OIPN.Copyright © 2022 Elsevier B.V. All rights reserved.