Periodontitis is a chronic inflammatory condition and one of the leading causes of tooth loss in adults worldwide. Traditional treatments mainly focus on plaque removal and antimicrobial strategies but often fall short in halting disease progression. Recent advances indicate that immune imbalance—specifically the skewed polarization of macrophages toward a pro-inflammatory state—plays a critical role in disease severity. Additionally, mitochondrial dysfunction and oxidative stress have been shown to hinder the transition of macrophages from inflammatory (M1) to reparative (M2) types, aggravating tissue destruction. Due to these challenges, new research has focused on modulating mitochondrial health and immune responses to combat periodontal disease.
A research team from Wenzhou Medical University and collaborating institutions has published a study (DOI: 10.1038/s41368-025-00360-0) on April 17, 2025, in the International Journal of Oral Science, revealing a novel therapeutic mechanism for treating periodontitis. The team demonstrated that dimethyl fumarate (DMF) protects gum tissue by improving mitochondrial function and altering macrophage polarization. Their findings identify Tu translation elongation factor (TUFM)-mediated mitophagy as a key pathway regulated by DMF, offering a promising strategy to combat this prevalent oral health issue through immune and mitochondrial modulation.
The study employed both in vivo and in vitro models to explore the role of DMF in periodontal disease. Mice with ligature-induced periodontitis were treated with DMF, resulting in significantly reduced bone loss and inflammation. Immunofluorescence and micro-CT scans confirmed improved alveolar bone density and suppressed osteoclast formation. At the cellular level, DMF treatment in RAW 264.7 macrophages decreased M1 markers (iNOS, IL-1β) and elevated M2 markers (Arg1, CD206). Additionally, DMF reduced oxidative stress by restoring mitochondrial membrane potential, ATP levels, and reactive oxygen species (ROS) balance.
Central to this mechanism is TUFM—a mitochondrial elongation factor. DMF preserved TUFM levels by inhibiting its ubiquitin-proteasome-mediated degradation. This preservation promoted mitophagy, thereby maintaining mitochondrial homeostasis. When TUFM was silenced using siRNA, DMF lost its protective effects, confirming TUFM’s crucial role. Notably, DMF also outperformed a known mitochondrial antioxidant, MitoQ, in restoring cellular function and macrophage balance. Collectively, these findings highlight DMF as a potent immunometabolic regulator capable of reprogramming macrophage responses and safeguarding periodontal tissues.
＂Dimethyl fumarate’s ability to fine-tune macrophage polarization through mitophagy is a game-changer in periodontal therapy,＂ said Dr. Shengbin Huang, the study’s corresponding author. ＂By targeting the mitochondrial protein TUFM, we uncovered a molecular switch that controls the inflammatory response in gum tissue. These insights could redefine how we treat chronic inflammatory conditions beyond the oral cavity.＂ The research opens the door for developing new localized therapies using DMF or similar compounds, especially in formulations designed to minimize systemic side effects.
This study paves the way for innovative treatments that go beyond traditional antimicrobial and mechanical approaches. By targeting TUFM-mediated mitophagy, DMF offers a method to restore mitochondrial health, reduce oxidative damage, and rebalance immune responses in periodontal tissue. Given DMF's existing approval for other diseases, its clinical translation could be accelerated. Future development may include hydrogel-based topical delivery systems to concentrate its effects in the gum region and minimize systemic exposure. These findings also open avenues for treating other inflammation-related diseases involving mitochondrial dysfunction and immune dysregulation.
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References
DOI
10.1038/s41368-025-00360-0
Original Source URL
https://doi.org/10.1038/s41368-025-00360-0
Funding Information
This work was supported by the following grants: Natural Science Foundation of China (grant nos. 82270991), Zhejiang Provincial Natural Science Foundation of China/Outstanding Youth Science Foundation (grant no. LR21H140002), Medical Health Science and Technology Major Project of Zhejiang Provincial Health Commission (grant no. WKJ-ZJ-2311), Wenzhou Science and Technology Bureau Public Welfare Social Development (Medical and Health) Science and Technology Project (grant no. ZY2021015), Opening Research Fund from Shanghai Key Laboratory of Stomatology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine (grant no. 2022SKLS-KFKT011), Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research (grant no. GXKLRROM2106), State Key Laboratory of Oral Diseases Open Fund (grant no. SKLOD2024OF08).
About International Journal of Oral Science
International Journal of Oral Science (ISSN 1674-2818) was founded in 2009 and aims to publish all aspects of oral science and interdisciplinary fields, including fundamental, applied and clinical research. Covered areas include oral microbiology, oral and maxillofacial oncology, cariology, oral inflammation and infection, dental stem cells and regenerative medicine, craniofacial surgery, dental materials, oral biomechanics, oral, dental and maxillofacial genetic and developmental diseases.