Available　evidence　indicates　that　neuregulin-1　(NRG-1)　can　provide　a　protection　against　myocardial　ischemia/　reperfusion　(I/R)　injury　and　is　involved　in　various　cardioprotective　interventions　by　potential　regulation　of　mitophagy.　However,　the　molecular　mechanisms　linking　NRG-1　and　mitophagy　remain　to　be　clarified.　In　this　study,　both　an　in　vivo　myocardial　I/R　injury　model　of　rats　and　an　in　vitro　hypoxia/reoxygenation　(H/R)　model　of　H9C2　cardiomyocytes　were　applied　to　determine　whether　NRG-1　postconditioning　attenuated　myocardial　I/R　injury　through　the　regulation　of　mitophagy　and　to　explore　the　underlying　mechanisms.　In　the　in　vivo　experiment,　cardioprotective　effects　of　NRG-1　were　determined　by　infarct　size,　cardiac　enzyme　and　histopathologic　examinations.　The　potential　downstream　signaling　pathways　and　molecular　targets　of　NRG-1　were　screened　by　the　RNA　sequencing　and　the　Protein-Protein　Interaction　Networks.　The　expression　levels　of　mitochondrial　uncoupling　protein　2　(UCP2)　and　mitophagy-related　proteins　in　both　the　I/R　myocardium　and　H/R　cardiomyocytes　were　measured　by　immunofluorescence　staining　and　Western　blots.　The　activation　of　mitophagy　was　observed　with　transmission　electron　microscopy　and　JC-1　staining.　The　KEGG　and　GSEA　analyses　showed　that　the　mitophagy-related　signaling　pathways　were　enriched　in　the　I/R　myocardium　treated　with　NRG-1,　and　UCP2　exhibited　a　significant　correlation　between　mitophagy　and　interaction　with　PINK1.　Meanwhile,　the　treatment　with　mitophagy　inhibitor　Mdivi-1　significant　eliminated　the　cardioprotective　effects　of　NRG-1　postconditioning　in　vivo,　and　the　challenge　with　UCP2　inhibitor　genipin　could　also　attenuate　the　activating　effect　of　NRG-1　postconditioning　on　mitophagy.　Consistently,　the　in　vitro　experiment　using　H9C2　cardiomyocytes　showd　that　NRG-1　treatment　significantly　up-regulated　the　expression　levels　of　UCP2　and　mitophagy-related　proteins,　and　activated　the　mitophagy,　whereas　the　challenge　with　small　interfering　RNA-mediated　UCP2　knockdown　abolished　the　effects　of　NRG-1.　Thus,　it　is　conclused　that　NRG-1　postconditioning　can　produce　a　protection　against　the　myocardial　I/R　injury　by　activating　mitophagy　through　the　UCP2/PINK1/LC3B　signaling　pathway.