PXD064291

PXD064291 is an original dataset announced via ProteomeXchange.

Title	GLP-1RA Ameliorates Polycystic Ovary Syndrome via Hypothalamic RASA1/AKT: A Novel pathway Linking Hyperandrogenism to GnRH Dysregulation
Description	Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia and hypothalamic-pituitary-gonadal (HPG) axis dysregulation involving gonadotropin-releasing hormone (GnRH) hyperactivity. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) show therapeutic promise in PCOS, their central regulation mechanisms remain unknown. Here, we demonstrate that GLP-1RA improves follicular maturation in PCOS via hypothalamic RASA1-dependent modulation of GnRH secretion. Based on our letrozole-induced PCOS rats, GLP-1RA was shown to restore hormonal homeostasis by normalizing testosterone, suppressing luteinizing hormone, and reinstating estrous cyclicity alongside ovarian recovery. Proteomics analysis revealed a substantial recovery from hyperandrogenism-induced hypothalamic dysregulation after GLP-1RA therapy. Landscapes of PCOS and GLP-1RA hypothalamic perturbations were systematically drawn. Crucially, subsequent network analysis identified RASA1-GnRH axis as a core axis underpins GLP-1RA related pharmacological rescue of PCOS hypothalamus. Bidirectional genetic perturbations of RASA1 in GnRH neurons rigorously confirmed RASA1's regulation over GnRH synthesis, as well as the mediating role of Ras/AKT in this pathway. Notably, the modulation of both RASA1 and Akt effectively counteracted testosterone-induced GnRH hypersecretion and reversed GLP-1RA treatment-mediated GnRH suppression, thereby fully establishing GLP-1RA’s pharmacological mechanism through RASA1-Ras/Akt-GnRH signaling axis. Our study represented the first investigation into the hypothalamic molecular mechanism by which GLP-1RA improves PCOS, highlighting RASA1 as a critical mediator of HPG axis in the female reproductive systems. The discovery of novel target in central control would serve as a promising therapeutic strategy for PCOS reproductive improvement beyond metabolic treatment.
HostingRepository	iProX
AnnounceDate	2025-05-26
AnnouncementXML	Submission_2025-05-26_19:50:45.287.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Linlin Yang
SpeciesList	scientific name: Rattus norvegicus; NCBI TaxID: 10116;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-26 01:16:26	ID requested
⏵ 1	2025-05-26 19:50:45	announced

Dataset with its publication pending

submitter keyword: GLP-1RA, GnRH, Hypothalamus, RASA1, PCOS

Linlin Yang
contact affiliation	Hebei Medical University
contact email	llyang@hebmu.edu.cn
lab head
Linlin Yang
contact affiliation	The first hospital of Hebei Medical University
contact email	llyang@hebmu.edu.cn
dataset submitter

iProX dataset URI