# Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin

## TL;DR

Ghrelin, once seen as a hunger hormone, is now understood to regulate many body functions and has potential for treating various diseases.

## Contribution

This review provides a comprehensive synthesis of ghrelin's structure, signaling, and systemic roles, highlighting its therapeutic potential.

## Key findings

- Ghrelin modulates glucose homeostasis, gastric motility, and innate immunity.
- Cryo-EM structures of GHSR1a reveal a bipartite binding pocket and biased signaling.
- Ghrelin influences neuroprotection, stress reactivity, and sleep, with implications for mental health.

## Abstract

Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a “hunger hormone” to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated “mini-ghrelins” can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the 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 responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin’s activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer’s disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches 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 the post-GLP-1 receptor agonist era.