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

  • Drug Des Devel Ther. 2026 May 22:20:599539. doi: 10.2147/DDDT.S599539.
Zhen Zhang  1 ,  Delong Niu  2 ,  Wenjie Qiu  3 ,  Haoyu Feng  1 ,  Lurong Jia  3 ,  Wenjuan Zhou  3
Affiliations
  • 1. School of Stomatology, Binzhou Medical University, Yantai, 264003, People's Republic of China.
  • 2. Department of Stomatology, Lanzhou Petrochemical General Hospital (The Fourth affiliated Hospital of Gansu University of Chinese Medicine), Lanzhou, 730060, People's Republic of China.
  • 3. Department of Oral Implantology, The Affiliated Yantai Stomatological Hospital, Binzhou Medical University, Yantai, 264003, People's Republic of China.
PMID: 42206237 DOI: 10.2147/DDDT.S599539
Abstract

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.

Keywords
Wnt5a/Ror2; diabetic periodontitis; ferroptosis; p38 MAPK pathway; semaglutide.
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