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.