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The cardiovascular-renal-liver-metabolic (CKLM) syndrome integrates dysmetabolically driven heart, vascular, kidney, and liver diseases through a shared pathophysiological substrate. In obesity, upregulation of the clearance natriuretic peptide receptor C (NPR-C) in adipose tissue creates a "NP deficiency," undermining the protective cardiovascular and metabolic actions of endogenous NPs. Recent preclinical data demonstrates that NPR-C functions beyond simple peptide clearance. Through interactions with ligands like CNP, musclin, and osteocrin, NPR-C triggers context-dependent intracellular signaling. In experimental models, independent of systemic NP levels, NPR-C directly modulates cardiac remodeling, podocyte injury, hepatic steatosis, vascular inflammation, and adipocyte function. This review synthesizes NPR-C biology within the CKLM framework. While human validation remains limited, targeting tissue-specific NPR-C pathways represents a promising therapeutic frontier for restoring cardiometabolic homeostasis.