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.　©　2022