BACKGROUND: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. Alpha-1 antitrypsin (AAT) has been identified as a prognostic factor for lung cancer survival. Proteolytic cleavage of AAT by specific enzymes generates C-terminal peptides with varying lengths and biological activities. So far, the role of these peptides in NSCLC progression and prognosis remains unexplored. In this study, we aim to investigate the prognostic potential of AAT peptides in patients with NSCLC. METHODS: Serum levels of the 9 peptides (C22, C36, C37, C39, C40, C42, C43, C44 and C45) were simultaneously quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Correlations between peptide levels and full-length AAT protein, clinical parameters, and patient outcomes were analyzed. Additionally, the potential of these peptides as prognostic markers was evaluated, and changes in the AAT-to-peptide ratio were assessed in relation to tumor progression. RESULTS: Peptides C36, C37, and C42 showed the highest levels and strong correlations with each other, AAT, a precursor of these peptides, and a trend-level association with C-reactive protein (CRP) levels. Notably, peptide levels were significantly associated with smoking status. In a multivariate Cox hazard model, C42 emerged as an independent prognostic factor for overall survival when combined with clinical parameters. Following surgical tumor resection, the concentrations of these peptides increased, along with their ratio to AAT, suggesting a tumor-related impact on AAT levels and its peptide generation. CONCLUSIONS: Our study highlights the potential prognostic value of AAT-derived peptides in NSCLC. Among the analyzed peptides, C36, C37, and C42 showed the strongest correlations with full-length AAT, and their levels were affected by smoking status. Notably, C42 emerged as an independent prognostic marker for overall survival.
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