Proteins from platelet-enriched preparations as candidate biomarkers for major depressive disorder: An exploratory...

Major depressive disorder (MDD) is a complex psychiatric disorder lacking objective clinical diagnostic biomarkers. Platelets express a variety of neuroactive proteins, including serotonin transporters and receptors, and are easily accessible in peripheral blood, making them a valuable surrogate tool for exploring molecular alterations underlying central nervous system diseases. This study aimed to screen proteins from platelet-enriched preparations as candidate biomarkers for distinguishing patients with MDD from healthy controls (HCs) and to preliminarily explore the potential biological mechanisms of platelets in MDD pathogenesis. A total of 20 patients with MDD and 20 age- and gender-matched HCs were enrolled. Data-independent acquisition (DIA)-based proteomic analysis identified 299 differentially expressed proteins in the platelet-enriched fraction between the two groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to characterize the functional profiles and signaling pathways of these altered proteins. Multiple machine-learning algorithms, including PLS-DA, LASSO regression, and SVM-RFE, were applied to screen optimal biomarker combinations. Finally, a four-protein panel consisting of C1QBP, DDX60, WDR81, and VPS37A showed favorable discriminatory potential for MDD, with consistent expression trends further examined in the validation cohort. The expression levels of this biomarker panel were correlated with HAMD scores in the pooled sample, which primarily reflected case-control differences. Within the MDD group, only C1QBP was significantly correlated with HAMD scores, whereas no significant correlations were observed for the other candidate proteins. Exploratory gender-stratified analysis further suggested potential gender-based heterogeneity in protein profiles of the platelet-enriched fraction among MDD individuals. In conclusion, this exploratory proteomic study identifies C1QBP, DDX60, WDR81, and VPS37A as potential candidate biomarkers from platelet-enriched preparations for MDD discrimination.