Background and purpose: Chronic obstructive pulmonary disease (COPD) is a global health burden leading to significant morbidity and mortality worldwide. CS exposure is a crucial driver to various progressive lung diseases including COPD and there is an unmet need of potential therapeutics. The present study examined to decipher the therapeutic role of TWEAK/Fn14 selective inhibitor aurintricarboxylic acid in COPD pathogenesis. Experimental approach: In vitro alveolar type II cells and macrophages were stimulated with cigarette smoke extract (CSE) followed by aurintricarboxylic acid (ATA) treatment. In vivo, rats were injected with CSE intraperitoneally twice a week for 16 weeks followed by ATA (10mg/kg) treatment for 4 weeks. Key results: Increased ROS generation, mitochondrial dysfunction in alveolar type II cells and nuclear translocation of NF-κB/p65 in macrophages were abrogated after ATA treatment. In vivo, lung inflammation induced by CSE followed by ATA treatment mitigated respiratory function impairment, immune cell infiltration, emphysema associated morphometric parameters and oxidative stress status. MALDI assessment of rat serum showed decreased CRP and related inflammatory proteins. In addition, ATA inhibited up-regulation of EMT related proteins including vimentin, α-SMA, and downstream transcription factor Snail via inhibition of β-catenin/wnt3a pathway. Furthermore, ATA reduced CSE-induced inflammatory makers including TNF-α, NF-κB and MAP kinases including p-p38, p-ERK1/2 and p-JNK in vitro and in vivo. Cumulatively, ATA enhanced lung regeneration and tissue repair by diminishing the inflammation and EMT transition. Hence, ATA can be a novel therapeutic candidate to reduce COPD associated pathological events and promote regeneration.