This study used proteomics-based data-independent acquisition (DIA) technology with the aim of screening for differential expression proteins in type I gastric neuroendocrine neoplasm (g-NEN).Differential expression proteins in type I g-NEN and peritumoral tissues were screened using DIA with liquid chromatography/tandem mass spectrometry (DIA-LC/MS/MS). The identified proteins were then functionally analysed using bioinformatics methods. We selected the three most highly expressed proteins, combined with patients' clinical data, for prognostic analysis.Compared with peritumoral tissues, 224 proteins were up-regulated, and 70 were down-regulated. The most significantly enriched biological processes and pathways were vacuolar proton-transporting V-type ATPase complex assembly and metabolism-related pathways. PCSK1, FBXO2, ACSL1, IRS2, and PTPRZ1 expression was markedly up-regulated in type I g-NENs. High IRS2 expression significantly correlated with a shorter time to recurrence.Our study provides a comprehensive proteomic signature based on DIA-LC/MS/MS and highlights high IRS2 expression as a potential prognostic marker for type I gNENs.© 2024 John Wiley & Sons Ltd.