摘要Diabetic kidney disease(DKD)is a major complication of diabetes mellitus,driven by hyper-glycemia-induced oxidative stress,ER stress,and mitochondrial apoptosis.This study ex-amined the protective effects of Morin against hyperglycemia-induced renal tubular injury,alone or in combination with the SGLT2 inhibitor Empagliflozin,with emphasis on the ATF6-DAPK1 axis.HK2 cells were exposed to high glucose with or without Morin and/or Em-pagliflozin.Cellular stress,mitochondrial function,and apoptosis were assessed.Morin-DAPK1 binding was examined via molecular docking,surface plasmon resonance(SPR),and cell thermal shift assay(CETSA).db/db mice received vehicle,Empagliflozin,Morin,or their combination for 14 weeks,followed by renal histological,biochemical,and metabolic evalu-ations.Morin reduced ROS accumulation,ER stress(p-PERK,p-eIF2α,CHOP,cleaved ATF6),mitochondrial dysfunction,and apoptosis in HK2 cells.It suppressed DAPK1 mRNA expres-sion via ATF6 inhibition and directly bound DAPK1(Kd=1.61 μmol·L-1),disrupting its inter-action with pro-apoptotic BAK/BIK.Empagliflozin indirectly downregulated DAPK1 through ER stress relief.Combination therapy synergistically reduced oxidative stress,preserved mi-tochondrial membrane potential,and prevented apoptosis.In db/db mice,both compounds improved renal structure,lowered blood glucose,reduced UACR,and inhibited kidney stress markers,with greater improvements in the combination group,which also alleviated hepatic steatosis.Morin exhibits renoprotective effects against high glucose-induced cellular stress and diabetic kidney disease,at least partially via DAPK1 targeting.Co-administration with Empagliflozin enhances these effects,supporting its potential as an adjunct therapy for hyper-glycemia-induced kidney injury.