Beyond glycemic control: How semaglutide reshapes intestinal neuroception via transforming growth factor-β/brain-derived neurotrophic factor signaling hubs

Table 1 Core molecular mechanisms of transforming growth factor-β/brain-derived neurotrophic factor signaling cascade activation by semaglutide

Pathway name	Key regulatory nodes and direction	Regulatory direction	Primary biological functions	Ref.
Semaglutide/GLP-1R/PI3K/Akt/GSK-3β/CREB/BDNF pathway	Semaglutide activates the GLP-1R, leading to enhanced PI3K/Akt signaling. This results in the inhibition of GSK-3β, which in turn promotes CREB activation and increases the transcription of BDNF	Positive activation	Promotes neuronal differentiation, synaptogenesis, and plasticity. Improves memory and cognitive function. BDNF, via TrkB receptor, initiates a positive feedback loop that reinforces PI3K/Akt signaling, creating a neuroprotective cycle	[33,35]
Bidirectional regulation of TGF-β signaling by semaglutide	In neuroinflammatory contexts, semaglutide elevates anti-inflammatory TGF-β levels and promotes microglial polarization toward the M2 phenotype. In fibrotic disease contexts, it downregulates the expression of TGF-β and its receptors, thereby inhibiting the epithelial-mesenchymal transition process	Bidirectional regulation	Anti-inflammatory: Attenuates neuroinflammation and promotes tissue repair in models like cerebral ischemia/reperfusion injury. Anti-fibrotic: Inhibits excessive extracellular matrix deposition and mitigates fibrosis progression in models of the liver	[8,36]

GLP-1R: Glucagon-like peptide-1 receptor; PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase B; GSK-3β: Glycogen synthase kinase-3β; CREB: Cyclic adenosine monophosphate-response element-binding; BDNF: Brain-derived neurotrophic factor; TrkB: Tropomyosin receptor kinase B; TGF-β: Transforming growth factor-β.

Table 2 In vitro and in vivo experimental evidence supporting the mechanisms of action of semaglutide

Evidence type	Experimental model	Intervention/treatment	Key findings and outcomes	Core targets/pathways involved	Ref.
In vitro	Human neuroblastoma SH-SY5Y cells	Treatment with GLP-1	Upregulated synaptic protein and neuronal receptor expression; blocked by PI3K inhibitor LY294002	PI3K/Akt signaling axis	[34]
	Hepatic stellate cell line LX-2	Exosomes derived from serum of T2DM patients treated with semaglutide	Reduced expression of fibrotic markers	TGF-β/Smad signaling pathway	[37]
In vivo	Streptozotocin-induced mouse model of sporadic Alzheimer’s disease	GLP-1 receptor agonist treatment	Increased hippocampal p-GSK-3β (Ser9), p-CREB (Ser133), and BDNF levels; decreased Aβ deposition and tau phosphorylation	GSK-3β/CREB/BDNF neuroprotective pathway	[33]
	High-fat diet-induced mouse model of diabetic cardiomyopathy	GLP-1RA	Inhibited cardiomyocyte lipid accumulation; downregulated TGF-β1, collagen I/III, and oxidative stress; attenuated myocardial fibrosis and improved cardiac function	TGF-β signaling; oxidative stress; fibrosis	[38]

GLP-1R: Glucagon-like peptide-1; PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase B; T2DM: Type 2 diabetes mellitus; TGF-β: Transforming growth factor-β; p-GSK: Phosphorylated glycogen synthase kinase-3β; p-CREB: Phosphorylated cyclic adenosine monophosphate-response element-binding; Aβ: Amyloid-β; CREB: Cyclic adenosine monophosphate-response element-binding; BDNF: Brain-derived neurotrophic factor; GLP-1RA: Glucagon-like peptide-1 receptor agonist.