To investigate the molecular mechanism of nobiletin(NOB) in protecting mice from renal ischemia-reperfusion injury(RIRI).Methods:Balb/c mice were assigned into sham，model，NOB(50 mg/kg)，silent information regulator 1(SIRT1) inhibitor EX527(5 mg/kg)，NOB+EX527(50 mg/kg nobiletin+5 mg/kg EX527) groups(n=6).Mice were treated with corresponding drugs 24 h before modeling.The RIRI model was established by blocking the blood flow of left renal artery and vein in mice.The content of oxidative stress markers in the kidney tissue was determined 24 h after modeling.Renal tissue lesions and fibrosis were evaluated by hematoxylin-eosin(HE) staining and Sirius red staining.Renal cell apoptosis was detected by terminal deoxynucleotidyl transferase(TdT) dUTP nick-end labeling(TUNEL).Western blotting was employed to determine the protein levels of SIRT1，forkhead box O3a(FOXO3a)，apoptosis，and autophagy-related proteins.The real-time fluorescence quantitative polymerase chain reaction was conducted to measure the mRNA levels of SIRT1 and FOXO3a in the kidney tissue.Results:Compared with the model group，the NOB group showed reduced degree of renal lesion and area of renal fibrosis，increased antioxidant capacity，decreased apoptosis，up-regulated mRNA and protein levels of SIRT1 and FOXO3a，up-regulated protein level of microtubule-associated protein LC3Ⅱ/LC3Ⅰ，and down-regulated protein level of p62 in the kidney tissue(all P<0.05).In addition，EX527 reversed the protective effect of NOB on the kidney.Conclusion:NOB relieves RIRI by activating autophagy mediated by SIRT1/FOXO3a signaling pathway.