Dimethyl Citraconate Alleviates Periodontitis via Activating the NRF2 Cascade.

Area of Science:

• Molecular Biology
• Immunology
• Pharmacology

Background:

• Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular defense against oxidative stress and inflammation.
• Citraconate isomers activate NRF2, with dimethyl citraconate (DMC) showing promise as a potent NRF2 agonist.

Purpose of the Study:

• To investigate the NRF2-activating potential of dimethyl citraconate (DMC).
• To evaluate the anti-inflammatory and therapeutic effects of DMC in a mouse model of periodontitis.

Main Methods:

• Assessed DMC's effect on intracellular NRF2 levels, nuclear translocation, and downstream gene expression.
• Utilized a ligation-induced periodontitis mouse model to evaluate DMC's therapeutic efficacy.
• Investigated the mechanism of NRF2 activation by examining DMC's interaction with KEAP1 and NRF2 stability.

Main Results:

• DMC significantly enhanced NRF2 stabilization and nuclear translocation, increasing antioxidant gene expression.
• Local administration of DMC ameliorated periodontal destruction and elevated NRF2 levels in vivo.
• The protective effects of DMC were dependent on NRF2, as demonstrated in Nfe2l2 knockout mice.
• DMC was found to prolong NRF2 half-life and promote its dissociation from KEAP1.

Conclusions:

• DMC is a potent activator of the NRF2 pathway, exhibiting significant anti-inflammatory properties.
• DMC demonstrates therapeutic potential for treating periodontal inflammation and related inflammatory conditions.