**Background**
Glucagon-like peptide-1 receptor (GLP-1R) signaling plays a critical role in regulating glucose homeostasis, appetite, and systemic inflammation. Beyond its primary role in treating type 2 diabetes and obesity, GLP-1R activation has demonstrated significant potential in treating neurodegenerative disorders and liver diseases. By penetrating the blood-brain barrier, GLP-1R agonists can exert neuroprotective effects, reduce oxidative stress, and modulate autophagy, making them valuable tools for studying Parkinson’s disease and other proteinopathies. Furthermore, these agents can regulate lipid metabolism and inhibit de novo lipogenesis in the liver, offering therapeutic avenues for metabolic dysfunction-associated steatotic liver disease (MASLD). In this context, we will introduce a long-acting, selective GLP-1R agonist – Semaglutide.
**Definition**
Semaglutide is a selective, competitive GLP-1R agonist that promotes insulin secretion, inhibits gastric emptying, and reduces appetite. According to the Semaglutide description, it is a long-acting peptide designed to enhance autophagy and inhibit apoptosis and oxidative stress.
**In Vitro and In Vivo Studies**
The Semaglutide biological activity has been extensively validated across various models. In vitro, Semaglutide (1-100 nM; 24 h) significantly increased the survival rate of SH-SY5Y human neuroblastoma cells against Aβ 25-35 injury by upregulating autophagy-related proteins (LC3II, Atg7, Beclin-1, P62) and the anti-apoptotic protein Bcl-2. In studies focusing on Semaglutide Cancer research, concentrations of 5-40 μM for 48 h dose-dependently inhibited the proliferation, migration, and invasion of Cal27 and HSC4 oral squamous cell carcinoma (OSCC) cells via activation of the P38 MAPK signaling pathway.
Semaglutide in vivo studies further demonstrate its versatility. In OSCC xenograft nude mouse models, subcutaneous injection (3 μmol/kg; 3 times weekly for 3 weeks) significantly reduced tumor volume and downregulated proliferation markers Ki67 and PCNA. In a chronic MPTP-induced Parkinson’s disease mouse model, intraperitoneal injection (25 nmol/kg; every 2 days for 30 days) improved motor dysfunction, increased TH-positive neurons, and reduced α-synuclein aggregation. Additionally, in MASLD mouse models, subcutaneous administration (25-100 μg/kg/week for 11 weeks) reduced body weight, blood glucose, and hepatic triglyceride deposition while downregulating de novo lipogenesis markers Acaca and Scd1. In conclusion, Semaglutide is a potent GLP-1R agonist with broad applications in metabolic, oncological, and neuroprotective research.
Keywords
Semaglutide, 1997361-85-9, GLP Receptor, Insulin Receptor, Autophagy, p38 MAPK, α-synuclein, Bcl-2 Family, Apoptosis, α-Syn, Inhibitor, inhibitor, inhibit
References
[1] Chang YF, et al. Semaglutide-mediated protection against Aβ correlated with enhancement of autophagy and inhibition of apotosis. J Clin Neurosci. 2020 Nov;81:234-239.
[2] Liu DX, et al. Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress. Parkinsons Dis. 2022 Jul 13;2022:6813017.
[3] Wang C, et al. Semaglutide, a glucagon-like peptide-1 receptor agonist, inhibits oral squamous cell carcinoma growth through P38 MAPK signaling pathway. J Cancer Res Clin Oncol. 2025 Mar 7;151(3):103.
[4] Zhang L, et al. Semaglutide is Neuroprotective and Reduces α-Synuclein Levels in the Chronic MPTP Mouse Model of Parkinson’s Disease. J Parkinsons Dis. 2019;9(1):157-171.
[5] Soto-Catalán M, et al. Semaglutide Improves Liver Steatosis and De Novo Lipogenesis Markers in Obese and Type-2-Diabetic Mice with Metabolic-Dysfunction-Associated Steatotic Liver Disease. Int J Mol Sci. 2024 Mar 4;25(5):2961.
[6] Stephen T Buckley, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018 Nov 14;10(467):eaar7047.