Dimethyl Citraconate Alleviates Periodontitis via Activating the NRF2 Cascade

Nuclear factor erythroid 2-related factor 2 (NRF2) is a pivotal transcription factor that regulates redox signaling, playing a protective role in inflammation. Citraconate is verified as the strongest NRF2 agonist among its isomers. Dimethyl citraconate (DMC), an esterified derivative of citraconate, holds the potential for activating NRF2 and relieving inflammation. Here, we show that DMC is a strong NRF2-activating compound, stabilizing the intracellular NRF2 level and its nuclear translocation. DMC increases the expression levels of NRF2 downstream genes, thereby restricting the accumulation of reactive oxygen species and performing anti-inflammatory functions. The local administration of DMC effectively alleviates periodontal destruction in a ligation-induced periodontitis mouse model, elevating the NRF2 levels and downstream antioxidant enzymes. Moreover, the protective effect of DMC against periodontitis is absent in <i>Nfe2l2^-/-</i> mice. Mechanically, DMC prolongs the half-life of NRF2 and facilitates its dissociation from KEAP1 (Kelch-like ECH-associated protein 1), which suggests that DMC interrupts the crosstalk between KEAP1 and NRF2. Collectively, our findings illustrate the role of DMC in activating NRF2 and ameliorating periodontal inflammation, suggesting its therapeutic potential for inflammation-related diseases.