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Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin
Polishchuk H, Guzik K, Kantyka T.. International journal of molecular sciences, 2025-11-13
Topic: Brain proteins, microglia and lab models
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.
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APA 7th
Polishchuk, H., Guzik, K., & Kantyka, T. (2025). Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin. International journal of molecular sciences. https://doi.org/10.3390/ijms262210996
Vancouver
Polishchuk H, Guzik K, Kantyka T. Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin. International journal of molecular sciences. 2025. doi:10.3390/ijms262210996. PMID: 41303478.
BibTeX
@article{polishchuk2025-41303478,
author = {Polishchuk, H. and Guzik, K. and Kantyka, T.},
title = {{Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin}},
journal = {International journal of molecular sciences},
year = {2025},
doi = {10.3390/ijms262210996},
pmid = {41303478},
url = {https://doi.org/10.3390/ijms262210996}
}
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Key findings
- 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.
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Study details
- Evidence strengthLow
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 26 of the 58 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (International journal of molecular sciences) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41303478) |
| Free to read | 2 / 2 | Free to read |
| Points | 26 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 26 of the 58 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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