In conclusion, our results revealed that the HDAC6-selective inhibitor CAY10603 inhibited CS-induced small airway remodelling by regulating epithelial barrier dysfunction and reversing EMT via the TGF-β1/Smad2/3 signalling pathway and CAY10603 treatment could significantly protect against CS-induced airway remodeling and emphysema. The gene discussed is SMAD2; the disease is pulmonary emphysema.