Circulating R-Spondin-1, Nesfatin-1, and Irisin in Gastric Cancer: A Biologically Complementary Multimarker Signature

Background/Objectives: Circulating biomarkers reflecting distinct aspects of tumor and host biology may provide complementary information in gastric cancer. We characterized serum R-Spondin-1, nesfatin-1, and irisin and explored whether their combined assessment improved case–control discrimination beyond individual markers. Methods: In this single-center case–control study, serum concentrations were measured by ELISA in 49 patients with histopathologically confirmed gastric adenocarcinoma and 50 age- and sex-frequency-matched apparently healthy controls; all samples were obtained before any gastric resection. Between-group differences were quantified using effect sizes and 95% confidence intervals. Associations with gastric cancer status were examined using Firth penalized logistic regression; discrimination was explored using ROC analysis with bootstrap internal validation. Results: R-Spondin-1 was higher in gastric cancer than in controls (14.03 ± 2.75 vs. 8.47 ± 2.48 ng/mL; Cohen’s d = 2.12), whereas nesfatin-1 (2.79 ± 0.88 vs. 4.19 ± 0.81 ng/mL; d = −1.65) and irisin (7.48 ± 2.18 vs. 11.52 ± 1.97 ng/mL; d = −1.95) were lower. Associations remained after adjustment. Individual AUCs were 0.926, 0.885, and 0.913; the exploratory three-marker signature yielded an AUC of 0.964 (95% CI 0.932–0.996) and an optimism-corrected AUC of 0.958. Results were materially similar in treatment-naive patients. Conclusions: Gastric cancer was associated with increased R-Spondin-1 and decreased nesfatin-1 and irisin. This pattern likely reflects tumor–host interaction, including mucosal and wasting-related contributions, rather than independent tumor-specific signals. These case–control estimates do not represent diagnostic accuracy, do not support early-detection use, and require prospective validation in clinically representative cohorts.