Systemic serological signatures and novel biomarker CST4 link CagA-positive Helicobacter pylori to broad systemic alterations.

Helicobacter pylori (H. pylori) virulence factors, particularly CagA, determine pathogenic outcomes, yet their systemic serological impact remains poorly characterized. This study aimed to delineate systemic serological signatures associated with CagA-positive H. pylori infection, evaluate the novel biomarker CST4 as an exploratory pathophysiological indicator of host response to virulent infection, and develop predictive nomograms integrating host and bacterial factors for gastric diseases. This retrospective study enrolled 565 participants who underwent bidirectional endoscopy with histopathological confirmation. H. pylori virulence-associated serotypes were identified using immunoblot analysis targeting CagA, VacA, UreA, and UreB proteins. Based on serological results, participants were categorized into three groups: Hp-negative, Hp I (positive for CagA and/or VacA), and Hp II (positive only for UreA and/or UreB). A comprehensive panel of serological parameters was assessed, including gastric function indicators (PG-I, PG-II, PG-I/II ratio, and G-17), inflammatory markers, lipid profiles, coagulation indices, tumor markers, and serum CST4 levels. Multivariate logistic regression analysis was performed to determine independent predictors, which were subsequently used to develop predictive nomograms. CagA-positive infection, particularly the CagA+VacA+ subtype, correlated with aggravated mucosal damage (elevated PG-II, reduced PG-I/II ratio, both P < 0.001). Serum CST4 levels were significantly elevated in Hp I patients (P = 0.032). The CST4-elevated group exhibited increased PG-I, PG-II, CA19-9, CA125, and D-dimer (all P < 0.05). CagA-positive infection was characterized by distinct systemic alterations: neutrophilia, elevated D-dimer and creatinine, shortened APTT, and reduced TC, HDL-C, and LDL-C (all P < 0.05). Younger age (OR = 0.976) and lower PG-I/II ratio (OR = 0.890) independently predicted Hp I infection. Three nomograms integrating host and bacterial factors demonstrated robust discrimination for gastric polyps (AUC = 0.808), ulcers (AUC = 0.796), and cancer (AUC = 0.709), with favorable calibration and net clinical benefit by decision curve analysis. CagA-positive H. pylori infection induces a distinct systemic serological signature encompassing pro-inflammatory, pro-coagulant, hypolipidemic, and renal alterations, extending pathogenic impact beyond the gastric niche. Serum CST4 emerges as a promising exploratory pathophysiological indicator reflecting host systemic response to virulent infection, supporting its utility in screening and risk triage, while lesion-specific prediction is better achieved by nomograms integrating direct bacterial and host factors. The validated nomograms enable individualized risk stratification, supporting optimized clinical triage in H. pylori-infected populations.