Effect of Lactate Metabolism on Hypoxia-induced Inflammation in the Oral Mucosa
- J Dent. 2026 Jun:169:106664. doi: 10.1016/j.jdent.2026.106664.
- 1. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
- 2. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China; School/Hospital of Stomatology, Lanzhou University, Lanzhou, Gansu 730000, China.
- 3. Department of Stomatology, The Third Affiliated Hospital of Henan Medical University, Xinxiang, Henan 453000, China.
- 4. Department of Stomatology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710000, China.
- 5. Dental College of Georgia, Augusta University, Augusta, GA 30912, USA.
- 6. Department of Stomatology, The Third Affiliated Hospital of Henan Medical University, Xinxiang, Henan 453000, China. Electronic address: [email protected].
- 7. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
- 8. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
Objectives: Acute exposure to hypoxemia is known to exacerbate oral mucosal inflammation; however, the underlying cellular and molecular mechanisms remain unclear. This study aimed to elucidate the molecular mechanisms by which acute hypoxia exacerbates oral mucosal inflammation and to evaluate the therapeutic potential of targeting lactate metabolism.
Methods: An acute hypoxia-induced oral mucosal inflammation model was established in vivo in mice and in vitro using oral mucosal fibroblasts. The signaling axis involving Wnt/β-catenin, Hypoxia-inducible factor 1-alpha (HIF-1α), and Lactate Dehydrogenase A (LDHA) was analyzed. The role of lactate was validated using specific inhibitors (galloflavin) and nicotinamide adenine dinucleotide (NAD⁺) supplementation. An animal model was established to verify the therapeutic efficacy of NAD⁺ in vivo.
Results: Acute hypoxia activated the Wnt/β-catenin pathway, which upregulated HIF-1α and LDHA expression, leading to accelerated lactate synthesis in fibroblasts. This lactate accumulation acted as a key mediator, amplifying nuclear factor kappa-B activation and subsequent inflammatory cytokine secretion. Crucially, inhibiting lactate generation or supplementing with NAD⁺ significantly attenuated inflammatory responses in vitro and alleviated oral mucosal damage in vivo.
Conclusions: Lactate metabolic reprogramming in fibroblasts is a central regulator of acute hypoxia-exacerbated oral inflammation. Targeting this metabolic axis via NAD⁺ offers a promising therapeutic strategy for managing hypoxic inflammatory diseases.
Clinical significance: The present study confirmed that acute hypoxia significantly aggravates oral inflammation through lactate-driven metabolic reprogramming. These findings provide a biological explanation for the increased severity of oral mucosal diseases in patients experiencing hypoxia (e.g., high altitude, sleep apnea) and suggest NAD⁺ supplementation as a novel intervention to mitigate mucosal injury.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Lactate DehydrogenaseResearch Areas: Cancer