Evodiamine　(EVO),　the　main　active　alkaloid　in　Evodia　rutaecarpa,　was　shown　to　exert　various　pharmacological　activities,　especially　anti-tumor.　Currently,　it　is　considered　a　potential　anti-cancer　drug　due　to　its　excellent　anti-tumor　activity,　which　unfortunately　has　adverse　reactions,　such　as　the　risk　of　liver　and　kidney　injury,　when　Evodia　rutaecarpa　containing　EVO　is　used　clinically.　In　the　present　study,　we　aim　to　clarify　the　potential　toxic　target　organs　and　toxicity　mechanism　of　EVO,　an　active　monomer　in　Evodia　rutaecarpa,　and　to　develop　mitigation　strategies　for　its　toxicity　mechanism.　Transcriptome　analysis　and　related　experiments　showed　that　the　PI3K/Akt　pathway　induced　by　calcium　overload　was　an　important　step　in　EVO-induced　apoptosis　of　renal　cells.　Specifically,　intracellular　calcium　ions　were　increased,　and　mitochondrial　calcium　ions　were　decreased.　In　addition,　EVO-induced　calcium　overload　was　associated　with　TRPV1　receptor　activation.　In　vivo　TRPV1　antagonist　and　calcium　chelator　effects　were　observed　to　significantly　reduce　body　weight　loss　and　renal　damage　in　mice　due　to　EVO　toxicity.　The　potential　nephrotoxicity　of　EVO　was　further　confirmed　by　an　in　vivo　test.　In　conclusion,　TRPV1-mediated　calcium　overload-induced　apoptosis　is　one　of　the　mechanisms　contributing　to　the　nephrotoxicity　of　EVO　due　to　its　toxicity,　whereas　maintaining　body　calcium　homeostasis　is　an　effective　measure　to　reduce　toxicity.　These　studies　suggest　that　the　clinical　use　of　EVO-containing　herbal　medicines　should　pay　due　attention　to　the　changes　in　renal　function　of　patients　as　well　as　the　off-target　effects　of　the　drugs.　©　2024