Abstract
BACKGROUND: Emerging evidence suggests metabolic syndrome (MetS) exacerbates sarcopenia progression and compromises nutritional interventions, yet its dual role as both etiological driver and therapeutic effect modifier remains uncharacterized. This study investigated MetS-related sarcopenia pathophysiology and assessed its impact on nutritional therapy efficacy in advanced gastric cancer. PATIENTS AND METHODS: We conducted a dual-phase investigation combining Mendelian randomization (MR) analysis of European-ancestry GWAS data (n = 654,783) with retrospective evaluation of 65 sarcopenic gastric cancer patients receiving chemotherapy and enteral nutrition. MR evaluated causal relationships between individual components of MetS and sarcopenia phenotypes, while clinical analyses compared outcomes by MetS status (IDF/AHA criteria). RESULTS: MR analysis of MetS components identified paradoxical causal effects: waist circumference increased appendicular lean mass (OR = 1.480, p < 0.001) but impaired walking speed (OR = 0.864, p < 0.001). In the clinical cohort, MetS patients exhibited accelerated nutritional decline with 2.6-fold greater weight loss (-1.70 vs. - 0.66 kg, p = 0.01), attenuated muscle preservation (48.1% vs. 73.7% SMI improvement, p = 0.066), and reduced median PFS (75.0 vs. 84.5 days, p = 0.061). Protein trajectories revealed MetS-specific catabolic patterns, particularly transferrin depletion (Δ = -0.26 vs. - 0.05 g/L, p = 0.0004). CONCLUSION: The integration of genetic and clinical findings shows that MetS components causally contribute to sarcopenia pathogenesis, and that the composite MetS phenotype confers nutritional therapy resistance. This establishes MetS's dual role as a driver of disease and a modifier of treatment efficacy.