Beyond Hunger: Structure, Signaling and Systemic Roles of Ghrelin

Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from a “hunger hormone” to a pleiotropic regulator of whole-body physiology. This review synthesizes current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, the high-potency GHSR1a agonist; des-acyl ghrelin predominates in circu-lation and exerts context-dependent, GHSR1a-independent or low-potency effects, while truncated “mini-ghrelins” can act as com-petitive antagonists. Emergence of synthetic ligands, agonists, antago-nists and reverse-agonists provided tools necessary to decipher of GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and pro-vide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond regulation of feeding and growth hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory re-sponses and promotes reparative macrophage phenotypes. In the emerging field of ghrelin activity in central nervous system, ghrelin in-fluences neuroprotection, stress reactivity, sleep architecture, and is implicated in depression, Alzheimer’s disease, and substance abuse disorders. Practical and transitional aspects are also highlighted: ap-proaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2–based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions and for obesity treatment in post–GLP-1 receptor agonist era.