Circadian clock-driven inter-organ crosstalk in cardiovascular-kidney-metabolic (CKM) syndrome: Molecular mechanisms, pathological progression, and chronotherapeutic strategies.

Cardiovascular-kidney-metabolic (CKM) syndrome is not merely the simple superimposition of isolated target organ lesions, but rather a systemic disorder sustained by a complex network of inter-organ communication. The circadian clock functions as the central spatiotemporal regulator of physiological homeostasis, and the circadian disruption is increasingly recognized as an important contributor to CKM progression. In this review, we systematically elucidate the core mechanisms and biological functions of the circadian clock in mediating inter-organ crosstalk within CKM syndrome. We first delineate the peripheral clock architecture in the heart, kidneys, and crucial metabolic organs, followed by an in-depth analysis of the molecular mediators governing spatiotemporal communication among these organs. Building upon this framework, we further dissect how circadian disruption drives the pathological transition from an early metabolic-inflammatory network imbalance to coupled cardiorenal vascular injury. Finally, we comprehensively summarize multidimensional intervention strategies, encompassing chronopharmacological optimization, lifestyle interventions, and small-molecule modulators targeting the core clock machinery. Ultimately, this review aims to offer a novel chronobiological perspective for decoding inter-organ pathological crosstalk in CKM syndrome, thereby providing a robust scientific rationale for developing circadian-aligned, precision, and multitarget synergistic therapies.