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Nesfatin-1 is a multifunctional peptide that integrates cardiovascular, metabolic, and immune regulation, particularly along the "Heart-Brain-Gut" axis. Accumulating evidence highlights its pivotal role in inter-organ communication under both physiological and pathological conditions. However, its underlying molecular mechanisms remain incompletely understood, and the prevailing orphan G protein-coupled receptor (GPCR) hypothesis is currently undergoing critical scrutiny due to accumulating data that contest its exclusivity and sufficiency in accounting for nesfatin-1's pleiotropic effects. This review provides a comprehensive synthesis of recent advances in these fields, with a focus on putative non-canonical signaling mechanisms and lipid rafts. By examining these non-canonical mechanisms and their implications for cellular cross-talk, we provide new insights into how nesfatin-1 coordinates multi-system integration. Furthermore, we discuss its translational relevance for precision medicine and targeted therapies against multi-organ diseases, proposing a comprehensive framework to guide future research and clinical applications.