Diagnostic Value of Serum GREM1 Levels in Differentiating Benign and Malignant Subsolid Pulmonary Nodules: A Prospective Observational Study

To evaluate the diagnostic value of serum gremlin 1 (GREM1) levels in differentiating benign from malignant subsolid pulmonary nodules, a clinically challenging CT phenotype, this prospective observational cohort study included 183 patients with subsolid (ground-glass) pulmonary nodules identified by thin-section chest CT and 100 age- and sex-matched healthy volunteers between January and December 2025. Patients were followed through the standard diagnostic pathway, and the final diagnosis was confirmed histopathologically. Serum GREM1 levels were quantified using ELISA. Receiver operating characteristic (ROC) curve analysis and multivariable binary logistic regression were used to evaluate diagnostic performance and factors associated with malignancy. Serum GREM1 levels increased stepwise from the healthy control group to the benign and malignant groups (all p < 0.05). The AUC of GREM1 for differentiating malignant nodules from benign nodules was 0.859, and the combined GREM1 and CYFRA21-1 model achieved an AUC of 0.918. Multivariable analysis revealed maximum nodule diameter, serum GREM1 level, and CYFRA21-1 level as independent risk factors associated with malignant nodules. Serum GREM1, particularly in combination with CYFRA21-1, may improve differentiation between benign and malignant subsolid pulmonary nodules. Further studies with larger samples and external validation are needed.