Fructose-diphosphate aldolase C as a novel diagnostic biomarker for early-stage non-small cell lung cancer: a low-abundance proteomics study.

BACKGROUND: Lung cancer remains one of the leading causes of cancer-related deaths worldwide. Early detection is crucial for improving prognosis and survival rates. This study aimed to identify the low-abundance plasma proteins as potential diagnostic biomarkers for early-stage non-small cell lung cancer (NSCLC) and to distinguish malignant from benign lung nodules. METHODS: Using a sodium-type Y zeolite-polymer polyanionic complex (NaY-PPC)-based low-abundance proteomics, we analyzed 181 plasma samples from healthy controls (HC; n=65), patients with benign lung nodules (BNs; n=21), and patients with early-stage NSCLC (n=95). Principal component analysis (PCA) and heatmap visualization were employed for differential analysis. The diagnostic performance of candidate biomarkers was evaluated using receiver operating characteristic (ROC) curves, and enzyme-linked immunosorbent assay (ELISA) was used for validation. Functional studies, including fructose-bisphosphate aldolase C (ALDOC) knockdown, were conducted to assess the role of ALDOC in NSCLC progression. RESULTS: We identified 23 significantly differentially expressed proteins, with ALDOC showing the most promising diagnostic potential. ALDOC could effectively distinguish NSCLC patients from HCs [area under the curve (AUC) =0.994] and from those with BNs (AUC =0.720). Combining ALDOC with the traditional biomarkers carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin fragment 21-1 (CYFRA21-1) improved the differentiation between NSCLC and BN (AUC =0.824). ELISA validation confirmed the findings from the proteomics analysis. Additionally, ALDOC was upregulated in NSCLC tissues, and its high expression correlated with poor overall survival. Knockdown of ALDOC significantly reduced NSCLC cell growth and motility, suggesting its tumor-promoting role. CONCLUSIONS: ALDOC is a promising diagnostic biomarker for early-stage NSCLC, with potential clinical utility in distinguishing malignant lung nodules from BNs. This study highlights the value of low-abundance proteomics in identifying novel biomarkers for lung cancer detection and risk assessment.