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Background Chronic gastric inflammation contributes to gastric carcinogenesis, but the relevance of systemic inflammatory proteins to gastric lesion progression and future gastric cancer (GC) risk remains unclear. We aimed to identify circulating inflammatory protein signatures associated with gastric lesion progression and incident GC, and to evaluate their potential for risk stratification.Methods Inflammatory proteomics was performed in a case-control study nested within the national Upper Gastrointestinal Cancer Early Detection program (UGCED, n=200) and a nested case-control study within the Mass Intervention Trial in Linqu, Shandong Province (MITS, n=300) ( IDDF2026-ABS-0454 Figure 1. Study workflow). Plasma and tissue samples were collected up to 12 years before GC diagnosis, and paired plasma samples at diagnosis were available for a subgroup. Inflammatory proteins associated with GC risk were identified in UGCED and prospectively validated in MITS. External validation was conducted in the UK Biobank Pharma Proteomics Project (UKB-PPP, n=48,011). Composite inflammatory protein scores (IPS), including overall, short-term, and long-term scores, were constructed to evaluate risk prediction.Results Nine inflammatory proteins were consistently associated with GC risk across discovery and validation stages. Five proteins were associated mainly with short-term GC risk within 6 years before diagnosis, whereas four proteins were associated with longer-term risk. A higher overall inflammatory protein score (O-IPS) was associated with increased GC risk in UGCED (odds ratio [OR]=2.35, 95% confidence interval [CI]: 1.59–3.47), MITS (OR=1.72, 95%CI: 1.30–2.27), and UKB (hazard ratio [HR]=1.33, 95%CI: 1.13–1.56). O-IPS increased further at GC diagnosis. Incorporation of proteomic features improved GC risk discrimination in both MITS and UKB. A favorable lifestyle attenuated the association between inflammatory protein scores and GC risk.Conclusions Systemic inflammatory protein signatures are associated with gastric lesion progression and GC risk across different time horizons. These circulating markers may improve GC risk prediction and support precision prevention strategies.Abstract IDDF2026-ABS-0454 Figure 1