Olink proteomics reveals immuno-inflammatory profile changes and potential regulatory mechanisms of non-suicidal self-injury behavior associated with depression in adolescent

Abstract Background N on- s uicidal s elf- i njury (NSSI) frequently co-occurs with adolescent depression. The underlying immunoinflammatory mechanisms and peripheral biomarkers remain poorly understood. This study aimed to identify plasma proteins associated with NSSI in depressed adolescents. We also explored the relevant immunoregulatory pathways and evaluated candidate diagnostic biomarkers for NSSI. Methods We used Olink proximity extension assay (PEA) proteomics to profile plasma samples from 20 a dolescent p atients w ith d epression (APwD), 20 a dolescent d epression w ith comorbid NSSI (ADwNSSI), and 20 m entally h ealthy c ontrols (MHC). NSSI scales assessed behavioral patterns and motivation. Results The ADwNSSI group scored significantly higher than the APwD group on NSSI-B2, NSSI-BM11, and NSSI-BP11 ( P < 0.05). Compared with MHC, APwD showed 11 differentially expressed proteins (DEPs), such as significantly up-regulated IL-17 A, IL10, and CCL19, and down-regulated IL13 and CCL11 ( P < 0.05). These DEPs were significantly enriched in inflammatory response, cytokine-mediated signaling, immune response, and cytokine activity. Compared with APwD, ADwNSSI showed 7 DEPs. Up-regulated proteins included MMP-1, OSM, HGF, VEGFA, and CASP-8 ( P < 0.05). Down-regulated proteins included CST5 and CD6 ( P < 0.05). KEGG analysis showed that these 7 DEPs were significantly enriched in TNF signaling, IL-17 signaling, and JAK-STAT signaling. ROC analysis showed that the 7-protein panel yielded an AUC of 0.825 in predicting NSSI. The 4-protein panel (CD6, CST5, VEGFA, and HGF) achieved an AUC of 0.800. Pearson and Mantel tests showed positive correlations between MMP-1, OSM, and VEGFA levels and NSSI indices such as NSSI-BP8, NSSI-BM6, and NSSI-B7 ( P < 0.05). Linear regression analysis confirmed these associations. MMP-1 correlated positively with NSSI behavioral motivation scores (NSSI-BM13, NSSI-BM14), OSM and VEGFA correlated positively with NSSI behavior scores (NSSI-B13, NSSI-B7) ( P < 0.05). Conclusion This study identified peripheral immunoinflammatory alterations and candidate biomarkers associated with NSSI in depressed adolescents. These findings provide a preliminary framework for understanding NSSI pathophysiology. Further independent validation is required to assess their clinical utility.