PGA3 (pepsinogen A3) is an aspartic-type endopeptidase with broad substrate specificity that preferentially cleaves bonds involving phenylalanine and leucine residues [UniProt]. As an inactive pepsin precursor, PGA3 functions in gastric proteolysis and is secreted into extracellular compartments including exosomes [GO Annotations]. Beyond its canonical digestive role, PGA3 serves as a biomarker for pathological aspiration. Elevated tracheal PGA3 levels correlate with altered respiratory microbiota composition, increased Prevotella and Candida abundance, and elevated pro-inflammatory cytokines (IL-1, IL-8), suggesting that gastroesophageal reflux-mediated PGA3 aspiration triggers respiratory dysbiosis and inflammation 1. In oncology, PGA3 is clinically relevant across multiple cancer contexts. It is upregulated in gastric cancer with bone metastasis and correlates with poor survival 2, and urinary PGA3 serves as a noninvasive biomarker for gastric cancer detection 3. PGA3 expression decreased in most cancer tissues compared to normal tissues, with differential prognostic implications across 33 tumor types 4. Additionally, urinary PGA3 demonstrates diagnostic utility in distinguishing benign prostate hyperplasia from prostate cancer (AUC=0.625) 5. Genetically, PGA3 exhibits copy number variation among human populations, suggesting adaptive selection during human evolution 6. PGA3 is part of a polymorphic gene family (PGA3, PGA4, PGA5) maintained through gene duplication events 7.