The relationship between energy production and cancer is attracting attention. This study aimed to investigate the clinicopathological significance of fumarate hydratase (FH), a tricarboxylic acid cycle enzyme, in gastric cancer using autoantibodies as biomarkers. The study analyzed 116 patients who underwent gastric cancer surgery and 96 healthy controls. Preoperative serum FH autoantibody (s-FH-Ab) titers were analyzed using an immunosorbent assay with an amplified luminescent proximity homogeneous assay. Receiver operating characteristic analysis was used to determine the cutoff s-FH-Ab titer. Clinicopathological factors and prognosis were compared between the high and low s-FH-Ab groups. The s-FH-Ab levels were significantly higher in the gastric cancer group than in the control group (p = 0.01). Levels were elevated even in patients with stage I gastric cancer compared with healthy controls (p = 0.02). A low s-FH-Ab level was significantly associated with distant metastasis (p = 0.01), peritoneal dissemination (p < 0.05), and poor overall survival (p < 0.01). Multivariate analysis revealed that low s-FH-Ab levels were an independent risk factor for poor prognosis (p < 0.01). Therefore, s-FH-Ab levels may be a useful biomarker for early diagnosis and the prediction of prognosis in patients with gastric cancer.

Background: Metabolic reprogramming toward aerobic glycolysis, commonly referred to as the Warburg effect, is a hallmark of cancer. Such metabolic alterations may lead to aberrant expression and release of glycolytic and mitochondrial proteins, which can act as tumor-associated antigens and elicit humoral immune responses. However, whether patients with esophageal carcinoma (EC) develop a broad autoantibody response against these metabolic proteins, and whether such an autoantibody profile has diagnostic or prognostic relevance, has not been systematically investigated. Objective: To determine (1) whether serum autoantibodies against 18 proteins involved in glucose metabolism and mitochondrial pathways are broadly elevated in patients with EC and have diagnostic potential; (2) whether combining selected autoantibodies improves diagnostic discrimination; and (3) whether individual or combined autoantibody profiles show exploratory associations with postoperative overall survival. Methods: Serum autoantibody levels against 18 metabolic proteins (SLC2A1, ASPSCR1, GK2, ALDOA, TPI1, GAPDH, PGK1, PGK2, ENO1, PGAM1, PKM, PDHB, PCK1, LDHA, SDHB, FH, IDH, and ATP5B) were measured in 191 patients with EC and 96 healthy donors using AlphaLISA. For diagnostic combination analysis, a multivariable logistic regression model combining ENO1-Ab, PDHB-Ab, and ALDOA-Ab was evaluated in the complete-case cohort. In 91 surgically treated patients, exploratory overall survival analyses were performed using Kaplan–Meier curves and log-rank tests after dichotomization of antibody levels. Results: All 18 autoantibodies were significantly elevated in patients with EC compared with healthy donors (all P < 0.05), with individual AUC values ranging from 0.593 for SDHB-Ab to 0.735 for ENO1-Ab. The three-autoantibody model combining ENO1-Ab, PDHB-Ab, and ALDOA-Ab achieved an AUC of 0.812 (95% CI, 0.751–0.873), with a sensitivity of 68.1% and a specificity of 83.9%, and showed significantly greater diagnostic discrimination than the individual autoantibodies evaluated in the same cohort. In exploratory postoperative overall survival analyses, PCK1-Ab and SDHB-Ab showed significant differences in overall survival by log-rank testing. Several combined autoantibody profiles were also associated with survival differences, including high ENO1-Ab/low PGAM1-Ab, high SDHB-Ab/low FH-Ab, high ALDOA-Ab/high TPI1-Ab, and high PCK1-Ab/high SDHB-Ab versus low PCK1-Ab/low SDHB-Ab. Conclusions: The consistent elevation of autoantibodies against all 18 evaluated metabolic proteins suggests the presence of a broad humoral immune response to metabolic antigens in patients with EC. A three-autoantibody model combining ENO1-Ab, PDHB-Ab, and ALDOA-Ab improved diagnostic discrimination compared with individual markers. Exploratory analyses also identified individual and combined autoantibody profiles associated with postoperative overall survival, warranting further validation in independent cohorts.