Inflammatory Adipokines and Potential Oxidative Stress-Related Mechanisms Linking MASLD with Subclinical...

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder linked to cardio-kidney-metabolic (CKM) syndrome, early vascular injury and redox imbalance. Inflammatory adipokines such as retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) may contribute to this hepatic-vascular interplay by integrating metabolic inflammation, oxidative stress and endothelial dysfunction. Therefore, the present study aimed to investigate the contribution of the inflammatory adipokines retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) to the hepatic-vascular interplay in MASLD within the cardio-kidney-metabolic (CKM) syndrome. Materials and Methods: We performed a systematic review and meta-analysis of studies evaluating circulating RBP4 and LCN2 levels in MASLD. PubMed, Scopus, and Web of Science were searched. Twenty studies were included in the qualitative synthesis, and ten in the quantitative meta-analysis. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Vascular findings were synthesized narratively because of heterogeneity in outcomes. Results: Circulating RBP4 levels were significantly higher in MASLD patients than in controls (SMD = 0.64, 95% CI: 0.08 to 1.20, p = 0.026; I² = 91.2%). LCN2 levels were also significantly elevated (SMD = 1.92, 95% CI: 0.83 to 3.00, p < 0.001; I² = 98.0%). Compared with RBP4, LCN2 showed a larger pooled effect size, although heterogeneity remained very high. In the qualitative synthesis, adipokines, particularly LCN2, were associated with markers of vascular injury, including carotid intima-media thickness, plaque burden, arterial stiffness, endothelial dysfunction, coronary severity, and cardiovascular events. Conclusions: Both RBP4 and LCN2 were elevated in MASLD, supporting a link between adipokine dysregulation and hepatic metabolic dysfunction within the broader cardio-kidney-metabolic (CKM) syndrome. LCN2 appeared to better reflect the inflammatory, metabolic, and vascular burden of disease. These findings support the view of MASLD as a systemic disorder within the CKM syndrome and highlight the potential of inflammatory adipokines as non-invasive biomarkers of integrated hepatic, metabolic, and vascular dysfunction.