Gelsolin as a diagnostic biomarker in non-small cell lung Cancer

Lung cancer is a major cause of cancer-related death, and its outcome is heavily reliant on the stage of diagnosis and biological heterogeneity. To enhance the imaging and tissue-based methodologies employed in risk stratification, indeterminate triage of pulmonary nodules, prognosis, and treatment monitoring, the integration of laboratory biomarkers is essential. Gelsolin (GSN) is a protein that binds to both calcium and actin, playing a crucial role in cytoskeletal remodelling, apoptosis, and intracellular signalling. It can be quantified in tumor tissues and biofluids using clinically scalable platforms. The initiation, invasion, and metastatic progression of non-small cell lung cancer (NSCLC) have been linked to altered expression of tissue gelsolin (GSN) and a reduction in plasma gelsolin (pGSN) levels, which exhibit an opposite directional change. This necessitates compartment-specific interpretation and control of inflammatory confounders. This review incorporates mechanistic and translational evidence on GSN in NSCLC, summarizing the biology of isoforms, actin complexes, pre-analytical variables, analytical platforms, and clinical evidence on the application of diagnostic, prognostic, and monitoring biomarkers. Specific attention is given to confounding diseases, including chronic obstructive pulmonary disease, infection, smoking, and critical illness, which alter pGSN levels and preclude its use as a diagnostic marker. We propose a framework to integrate tissue and circulating GSN biology, alongside the preanalytical and analytical standardization requirements and the necessary actions to implement GSN as an auxiliary, mechanism-based biomarker in clinical chemistry. This includes standardized measurands, commutable calibrators, multicenter validation, and positioning within low-dose lung cancer care pathways.