Adipokines and Vascular Modulators in CKM: Emerging Biomarkers as Diagnostic and Therapeutic Targets.

Cardio-kidney-metabolic (CKM) syndrome represents an integrated clinical and molecular continuum encompassing metabolic dysfunction, cardiovascular disease and chronic kidney disease. This multidimensional disorder arises from interdependent biological pathways that extend beyond conventional risk factors. Emerging evidence highlights a group of adipokines and vascular modulators-including retinol-binding protein 4 (RBP4), lipocalin 2 (LCN2), apolipoprotein M (ApoM), Klotho and matrix Gla protein (MGP)-emerging molecular modulators with potential involvement in CKM pathophysiology. Pro-inflammatory adipokines such as RBP4 and LCN2 contribute to insulin resistance, oxidative stress and endothelial dysfunction. In contrast, protective molecules including ApoM and Klotho preserve nitric oxide bioavailability, lipid metabolism and antioxidant defense. MGP modulates vascular calcification and adipose remodeling, with its inactive form (dp-ucMGP) linked to vascular stiffness and renal decline. The combined dysregulation of these molecules sustains cycles of inflammation, oxidative stress and tissue remodeling that drive CKM progression. Collectively, current data support their dual role as biomarkers and therapeutic targets. Nonetheless, clinical translation remains limited, emphasizing the need for standardized assays, longitudinal validation, and integrative multimarker approaches within precision medicine frameworks for CKM syndrome.