Semaglutide Inhibits Osteoblast Ferroptosis Induced by Diabetic Periodontitis via Modulating the Wnt5a/Ror2/p38 MAPK Signaling Pathway.

BACKGROUND

Type 2 diabetes mellitus (T2DM) is a major risk factor for periodontitis, often leading to exacerbated alveolar bone loss. Ferroptosis, an iron-dependent regulated cell death pathway, contributes to osteoblast dysfunction under diabetic conditions. The non-canonical Wnt5a/Ror2 pathway is pivotal in inflammation and bone metabolism. Semaglutide, a long-acting GLP-1 receptor agonist, may modulate this pathway and protect osteoblasts from ferroptosis, however, its role in diabetic periodontitis remains unclear.

METHODS

MC3T3-E1 osteoblasts were exposed to high glucose plus palmitic acid (HGHP) to mimic a diabetic microenvironment. The effects of Semaglutide on osteoblast proliferation, migration, differentiation, mineralization, and ferroptosis were assessed using EDU, Transwell, ALP and ARS staining, qPCR, Western blotting, ROS, Fe2⁺, and lipid peroxidation assays. Mechanistic involvement of Wnt5a/Ror2/p38 MAPK signaling was examined using Wnt5a siRNA and a p38 MAPK agonist. In vivo, T2DM mice with ligature-induced periodontitis were treated with semaglutide; alveolar bone and ferroptosis-related markers were assessed by H&E, immunohistochemistry (OPN, GPX4), and 4-HNE immunofluorescence.

RESULTS

HGHP induced osteoblast ferroptosis, increased oxidative stress, and impaired osteogenic function. Semaglutide restored proliferation and osteogenic capacity and attenuated oxidative stress and ferroptosis. Wnt5a was upregulated by HGHP; its silencing reduced ferroptosis and improved osteogenesis. Semaglutide suppressed HGHP-induced Wnt5a/Ror2/p38 MAPK activation, whereas p38 activation blunted its protective effects. In T2DM periodontitis mice, semaglutide reduced periodontal inflammation and osteoblast ferroptosis.

CONCLUSION

Semaglutide mitigates HGHP-induced osteoblast ferroptosis and improves osteogenic function via the Wnt5a/Ror2/p38 MAPK pathway, supporting its potential in diabetic periodontitis.