Airway　epithelial　mitochondrial　oxidative　stress　and　damage　is　an　important　pathology　in　chronic　obstructive　pulmonary　disease　(COPD).　Mitophagy　involves　MAPK15-ULK1　signaling,　the　role　of　which　is　unknown　in　COPD.　This　study　investigated　MAPK15-ULK1　signaling　in　airway　epithelial　cells　of　COPD　patients　and　its　activation　by　cigarette　smoke　extract　(CSE)　in　isolated　human　airway　epithelial　cells.　Significant　increased　phosphorylation　of　MAPK15　and　ULK1　(Ser555)　was　detected　in　the　airway　epithelium　of　COPD　patients.　This　pathology　was　maintained　in　isolated　primary　COPD-epithelial　cells.　Compared　to　control　cells,　the　protein　expression　of　Beclin1　and　the　ratio　of　LC3II　to　LC3I　were　both　significantly　increased　in　COPD-epithelial　cells.　In　human　airway　epithelial　cells,　CSE　significantly　increased　the　phosphorylation　of　MAPK15,　ULK1　(Ser555),　the　expression　of　Beclin1,　and　the　LC3II/LC3I　ratio　in　a　concentration-and　time-dependent　manner.　Transfection　with　MAPK15　siRNA　significantly　inhibited　the　CSE-induced　ULK1　(Ser555)　phosphorylation　in　airway　epithelial　cells.　Silencing　of　MAPK15　or　ULK1　significantly　reduced　CSE-induced　mitophagy　and　mitochondrial　oxidative　stress,　thereby　improving　cell　viability.　In　summary,　cigarette　smoke　activated　MAPK15-ULK1　signaling,　thereby　promoting　mitophagy　and　mitochondrial　oxidative　stress　in　airway　epithelial　cells.　This　signaling　pathway　is　activated　in　COPD-epithelial　cells　and　therefore　might　present　a　novel　therapeutic　target　for　COPD.