Sarcopenia, broadly characterized by the progressive loss of skeletal muscle mass and functional deterioration, is a prevalent comorbidity in cancer patients, affecting 30–60% of individuals across tumor types (1). It is strongly associated with increased chemotherapy toxicity, reduced treatment tolerance, and poorer survival outcomes (2, 3). While malnutrition has long been recognized as a key driver of sarcopenia, emerging evidence highlights metabolic dysregulation—particularly MetS, a cluster of conditions including central obesity, hypertension, and dyslipidemia—as an independent risk factor (4–6). According to the Asian-specific criteria established by the International Diabetes Federation (IDF) and the Asian Pacific Society of Cardiology (APSC), metabolic syndrome is defined by central obesity with ethnicity-adjusted waist circumference thresholds (≥90 cm for Asian men or ≥80 cm for Asian women), plus at least two of the following: elevated triglycerides, reduced HDL cholesterol, hypertension, or impaired fasting glucose (7, 8). These metabolic abnormalities share pathophysiological pathways with sarcopenia, such as chronic inflammation, mitochondrial dysfunction, and insulin resistance, creating a vicious cycle that exacerbates muscle catabolism (9).

Despite advances in understanding these interactions, critical gaps persist. While observational studies consistently associate MetS components with muscle loss (e.g., waist circumference, hypertension) and muscle loss (10, 11), the causal nature of this relationship remains uncertain due to inherent limitations of traditional epidemiological approaches (12). Furthermore, although enteral nutrition (EN) is widely recommended for cancer-related sarcopenia (13), its efficacy in patients with concurrent metabolic dysfunction requires clarification - particularly in gastric cancer where sarcopenia prevalence reaches 50% and significantly impacts the 350,000 annual new cases in China. While EN benefits early postoperative patients (14), its role in advanced disease, especially regarding potential mitigation of MetS-exacerbated muscle catabolism through inflammatory and insulin resistance pathways, remains poorly characterized.

To address these gaps, we employed a dual-method approach integrating causal inference with clinical validation. Using MR with genetic variants as instrumental variables, we established causal effects of MetS components on muscle function. Complementing these findings, our retrospective cohort study of advanced gastric cancer patients with sarcopenia evaluated EN efficacy stratified by MetS status. This integrated investigation not only clarifies the causal role of metabolic dysregulation in sarcopenia pathogenesis but also provides clinically actionable insights into how metabolic status modifies nutritional intervention outcomes, informing more personalized management strategies for cancer-associated sarcopenia.

This integrated investigation employing MR and clinical cohort analyses provides novel insights into the dual role of MetS as both an etiological driver and therapeutic effect modifier in sarcopenia pathogenesis. Our MR analysis, focused on individual components of MetS, revealed a defining paradox: genetic predisposition to higher waist circumference exerted dual causal effects, increasing appendicular lean mass and grip strength yet simultaneously decreasing walking speed. A similar detrimental causal effect was observed for hypertension on walking speed. Our clinical findings further demonstrated that MetS is associated with preserved muscle mass but attenuated therapeutic benefits. These observations challenge conventional sarcopenia paradigms and underscore the complex interplay between metabolic dysregulation and muscle biology. A key consideration is the difference in populations between the genetic (European-ancestry GWAS) and clinical (Chinese cohort) analyses. While this precludes direct generalization, the biological pathways implicated are fundamental across populations. Thus, the clinical findings demonstrate that the pathophysiological process, for which MR provides causal evidence at the component level, is operational and impactful as a syndromic entity in a distinct, high-risk patient setting.

The sarcopenic obesity paradox provides the key conceptual framework for reconciling these seemingly discordant results. The detrimental impact of MetS components on walking speed aligns with established mechanisms linking insulin resistance and chronic inflammation to muscle quality decline. Specifically, the robust association between hypertension and functional impairment (OR = 0.985) suggests vascular mechanisms may underpin sarcopenia pathogenesis, where endothelial dysfunction and capillary rarefaction compromise muscle perfusion—a hypothesis supported by recent demonstrations of impaired nitric oxide bioavailability in MetS-related myopathy (24). The paradoxical increase in appendicular lean mass (OR = 1.480), rather than being an outlier, is a hallmark of this paradox, where greater absolute muscle mass may not confer functional benefit due to often concomitant impairments in muscle quality. This finding likely reflects adipose-muscle crosstalk, where visceral fat-derived follistatin-like 1 (FSTL1) antagonizes myostatin activity to promote muscle hypertrophy, albeit at the cost of inducing insulin resistance (25). This metabolic trade-off creates a “pseudo-sarcopenic” phenotype where quantitative muscle mass metrics mask functional deficits, necessitating revised diagnostic criteria incorporating dynamometric assessments.

Clinical analyses incorporating fixed effects of time, metabolic syndrome status, and their interactions revealed significant therapeutic response heterogeneity across key parameters. Weight, total protein (TP), and transferrin (TRF) demonstrated robust MetS-dependent differential responses (p _interaction<0.05), while skeletal muscle index (SMI), prealbumin (PA), and albumin (ALB) showed non-significant trends for interactions (0.05 < p _interaction<0.10), collectively indicating MetS attenuates therapeutic efficacy across nutritional and musculoskeletal metrics. The diminished therapeutic efficacy in MetS patients was most pronounced in weight dynamics (−1.70 kg vs. −0.66 kg loss) and iron metabolism, evidenced by MetS-specific transferrin depletion (Δ = −0.26 vs. −0.05 g/L), likely mediated through chronic inflammation-driven hepcidin overexpression that restricts iron mobilization (26). Concurrent declines in hepatic synthetic markers—albumin (Δ = −0.82 g/dL) and prealbumin (Δ = −2.74 mg/L)—mirror patterns observed in NAFLD progression (27), suggesting MetS exacerbates subclinical liver dysfunction. These proteomic perturbations coalesce into a malnutrition-inflammation axis where sustained catabolic signaling, potentially via IL-6-mediated JAK/STAT activation (28), overrides nutritional anabolism, establishing MetS as both a biological filter and amplifier of therapeutic resistance.

Although our clinical cohort could not directly assess physical function, the observed MetS-associated resistance to nutritional therapy—manifested as attenuated muscle mass preservation and profound catabolism—likely represents the physiological counterpart to the impairment in walking speed identified by the MR analysis. Both findings converge to indicate that MetS predisposes to a more severe and treatment-refractory sarcopenia phenotype. This is further reflected in the 9.5-day PFS reduction in MetS patients (75.0 vs. 84.5 days), which extends the clinical implications beyond sarcopenia management to cancer therapeutics. We postulate that MetS-induced gut barrier dysfunction (29) may alter chemotherapeutic agent bioavailability, while elevated free fatty acids compete with albumin-bound chemotherapeutic agents (e.g., taxanes, irinotecan) for protein binding (30)—mechanisms requiring validation through pharmacokinetic studies. The differential toxicity profiles observed suggest metabolic status should inform risk stratification in treatment protocols.

The integrative pathophysiological model presented in Figure 6 provides a framework for understanding how MetS creates a biological context that exacerbates sarcopenia and confers resistance to nutritional therapy, ultimately impacting cancer outcomes.

Several limitations warrant consideration. First, the European ancestry of MR data limits the generalizability of the genetic findings to diverse populations. Second, the clinical cohort’s modest sample size, particularly in the MetS subgroup (n = 27), reduces statistical power and increases the risk of Type II errors. As a result, the observed non-significant trends (e.g., in SMI and PFS]) should be interpreted as hypothesis-generating rather than conclusive findings. Third, the narrow patient population (advanced metastatic gastric cancer with sarcopenia) limits external validity to other cancer types or stages. Fourth, the retrospective design necessitated reliance on CT-based sarcopenia criteria, which precluded assessment of muscle function and direct validation of the MR-based functional outcomes.

Future investigation should prioritize multi-ethnic MR analyses to disentangle genetic vs. environmental MetS effects and incorporate objective functional assessments like gait speed into sarcopenia diagnostics. Furthermore, future studies should incorporate assessments of metabolic dysfunction-associated steatotic liver disease (MASLD), utilizing promising biomarkers such as plasma homocysteine and the atherogenic index of plasma to elucidate its shared mechanisms with sarcopenia (31, 32). Mechanistic studies exploring adipose-derived exosomes’ role in muscle metabolism could clarify the obesity paradox. Clinically, trials combining GLP-1 agonists with high-protein nutritional support may counter MetS-related anabolic resistance, leveraging their dual metabolic and anti-inflammatory properties.

In conclusion, this study repositions MetS as both a catalyst and amplifier of sarcopenia pathophysiology. The findings mandate a paradigm shift in sarcopenia management—from generic nutritional support to precision strategies addressing individual metabolic profiles. While enteral nutrition remains foundational, its efficacy appears contingent on metabolic health status, underscoring the imperative for combinatorial approaches targeting insulin signaling, inflammation, and mitochondrial function in high-risk MetS populations.