| Sumario: | Background: Cancer cachexia (CAC) is a prevalent and debilitating complication in gastric cancer. However, specific tumor‐derived biomarkers for the screening and diagnosis of CAC remain largely unidentified. This study was designed to screen cachectic factors secreted by tumors and to investigate the value of regenerating islet‐derived family member 4 (REG4) in CAC. Methods: We enrolled 91 gastric cancer patients, stratified into a CAC group (n = 34) and a noncachectic (NC) group (n = 57). To identify cachectic factors differentially expressed by tumor tissues, bulk RNA sequencing was performed. REG4 expression was validated in tumor tissues and plasma using immunohistochemistry and enzyme‐linked immunosorbent assay, respectively. CT imaging was utilized to evaluate body composition parameters, specifically the skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI). The relationships among plasma REG4 levels, nutritional status, and body composition were analyzed. Logistic regression analysis was employed to identify risk factors for CAC, and receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic value of REG4. Results: RNA sequencing revealed significantly elevated REG4 gene expression in the gastric cancer tumors from the CAC group compared with the NC group. Plasma REG4 levels in the CAC group were significantly higher (p < 0.001). Correlation analysis demonstrated that elevated plasma REG4 was significantly associated with lower SMI (r = −0.24, p = 0.02), SATI (r = −0.26, p = 0.01), BMI (r = −0.26, p = 0.01), and prealbumin (r = −0.22, p = 0.04), as well as increased 6‐month weight loss (r = 0.36, p < 0.001). Multivariate logistic regression and ROC curve analysis identified high REG4 levels as an independent risk factor (OR = 7.54, 95% CI: 2.63–21.65) and a potential predictor for CAC (AUC = 0.728, 95% CI: 0.626–0.831, p < 0.001). Conclusion: In patients with gastric cancer, tumor‐derived REG4 is released into the circulation, resulting in elevated plasma levels that correlate with poor nutritional status and compromised body composition. Circulating REG4 holds promise as a novel predictor for the clinical diagnosis of CAC.
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