Discovery and Validation of Lung Cancer Biomarkers Based on Proteomic Analysis of Bronchoalveolar Lavage Fluid from the Self-Controlled Pulmonary Lobes

Distinguishing indeterminate pulmonary nodules remains a significant challenge in the early diagnosis of lung cancer. This study aims to identify lobe-specific proteomic biomarkers to address this issue. Using a data-independent acquisition (DIA) strategy, we performed proteomic profiling of bronchoalveolar lavage fluid (BALF) obtained from the lesioned lobe of lung cancer patients (LC-L), their paired nonlesioned lobe (LC-N), and the lesioned lobe of patients with benign nodules (BN-L). We quantified 4,305 proteins and identified 134 upregulated and 44 downregulated proteins in LC-L compared to both control groups (p < 0.05; |FC| > 1.2). Pathway analysis revealed significant enrichment of these dysregulated proteins in metabolic pathways and the TCA cycle. Subsequent validation in an independent cohort confirmed that two candidate proteins, SUCLA2 and FKBP9, were significantly upregulated specifically in cancerous lobes. To our knowledge, this is the first report identifying SUCLA2 and FKBP9 as lung cancer-specific biomarkers detectable in BALF using a self-controlled study design. These findings provide crucial insights into the metabolic reprogramming of early stage lung cancer and offer promising novel targets for improving the differential diagnosis of indeterminate pulmonary nodules.