Cardiovascular-kidney-metabolic syndrome: novel molecular mechanism and glucagon-like peptide-1-targeting therapy.

Cardiovascular-kidney-metabolic (CKM) syndrome represents a systemic disease continuum arising from the progressive and reciprocal interactions among metabolic dysfunction, kidney injury, and cardiovascular disease. Obesity and type 2 diabetes mellitus (T2DM) are major metabolic drivers of early CKM progression and contribute to cardiac and kidney injury through insulin resistance, glucotoxicity and lipotoxicity, chronic inflammation, oxidative stress, mitochondrial dysfunction, and ectopic lipid deposition, thereby establishing a self-reinforcing vicious cycle across the metabolic, cardiovascular, and renal systems. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) not only participate in the regulation of glucose homeostasis and energy metabolism but also represent an important regulatory nexus linking metabolic dysfunction to cardiorenal injury. GLP-1 receptor agonists (GLP-1RAs) improve metabolic homeostasis by enhancing glucose-dependent insulin secretion, suppressing glucagon release, reducing appetite and body weight, and decreasing visceral and ectopic fat accumulation. In parallel, they may exert renal and cardiovascular protective effects by improving endothelial function and microcirculation, suppressing inflammation and oxidative stress, maintaining mitochondrial homeostasis, and attenuating fibrosis. In recent years, large-scale clinical studies have further extended the benefits of GLP-1RAs beyond glycaemic control and weight reduction to improved kidney outcomes, reduced major cardiovascular events, and benefits in obesity-related heart failure with preserved ejection fraction. Meanwhile, natural products, characterised by multi-component, multi-target, and multi-pathway actions, may provide a complementary strategy for integrated CKM management by simultaneously improving glucose and lipid metabolic disturbances, insulin resistance, inflammation, and oxidative stress, while attenuating cardiac remodelling, kidney injury, and fibrosis. Emerging studies have shown that some natural products can concurrently improve metabolic, cardiac, and renal phenotypes in CKM-related diseases or composite disease models. This review focuses on the interactions among the metabolic, renal, and cardiovascular systems in CKM, summarises the biological basis and signalling mechanisms of the GLP-1/GLP-1R system, and highlights the mechanistic and clinical evidence supporting GLP-1RA-mediated protection against obesity- and T2DM-related metabolic dysfunction and cardiorenal injury. The potential value of natural products in comprehensive CKM intervention and future research directions are also discussed.