SERPINA1 encodes alpha-1-antitrypsin (A1AT), a serine protease inhibitor with critical roles in protecting the lower respiratory tract. The primary function is reversible inhibition of human leukocyte elastase and other proteases, particularly chymotrypsin, while sparing trypsin 1. A1AT is synthesized in hepatocytes and circulates systemically, localizing to the extracellular matrix and extracellular spaces where it prevents proteolytic tissue destruction. Mutations in SERPINA1, particularly the common S and Z alleles, cause alpha-1-antitrypsin deficiency (AATD), an autosomal recessive disorder affecting approximately 1 in 1,500-3,500 individuals 2. Z allele mutations lead to misfolded protein accumulation in hepatocytes, triggering endoplasmic reticulum stress and both hepatic and pulmonary disease 1. Homozygous ZZ individuals face severe deficiency with early-onset emphysema, particularly in smokers, and progressive liver fibrosis 3. Heterozygous carriers (MZ, SZ) show increased disease risk only with additional environmental factors. Clinically, AATD is significantly underdiagnosed and frequently misattributed to COPD or cryptogenic liver disease 4. Current treatment options are limited; augmentation therapy with plasma-derived A1AT can delay emphysema progression in eligible patients 3. Emerging therapies including gene therapy, induced pluripotent stem cells, and RNA editing approaches targeting pathogenic variants show promise 5. Genetic testing via SERPINA1 sequencing is recommended for all COPD patients at diagnosis to enable early intervention 4.