Proteomic alterations preceding the onset of depression offer valuable insights into its development and potential interventions.Leveraging data from 46,165 UK Biobank participants and 2920 plasma proteins profiled at baseline,we conducted a longitudinal analysis with a median follow-up of 14.5 years to explore the relationship between plasma proteins and incident depression.Linear regression was then used to assess associations between depression-related proteins and brain structures,genetic factors,and stress-related events.Our analysis identified 157 proteins associated with incident depression(P<1.71×10^(-5)),including novel associations with proteins such as GAST,PLAUR,LRRN1,BCAN,and ITGA11.Notably,higher expression levels of GDF15(P=6.18×10-26)and PLAUR(P=2.88×10^(-14))were linked to an increased risk of depression,whereas higher levels of LRRN1(P=4.28×10^(-11))and ITGA11(P=3.68×10^(-9))were associated with a decreased risk.Dysregulation of the 157 proteins is correlated with brain regions implicated in depression,including the hippocampus and middle temporal gyrus.Additionally,these protein alterations were strongly correlated with stress-related events,including self-harm events,adult,and childhood trauma.Biological pathway enrichment analysis highlighted the critical roles of the immune response.EGFR and TNF emerged as key proteins in the protein-protein interaction network.BTN3A2,newly linked to incident depression(P=4.35×10^(-10)),was confirmed as a causal factor through Mendelian randomization analysis.In summary,our research identified the proteomic signatures associated with the onset of depression,highlighting its potential for early intervention and tailored therapeutic avenues.