Mechanistic and Therapeutic Insights into Nrf2-Mediated Redox Regulation in Periodontitis

Periodontitis is a chronic non-communicable inflammatory disease in which oxidative stress plays an important role in tissue destruction and alveolar bone loss. Excessive production of reactive oxygen species disrupts redox homeostasis, activates inflammatory signaling pathways, and promotes regulated cell death processes such as pyroptosis and ferroptosis. The Nrf2/Keap1 pathway is a key regulator of antioxidant defense and cellular adaptation to redox imbalance. Impaired Nrf2 signaling has been associated with enhanced oxidative injury, NF-κB and NLRP3 inflammasome activation, osteoclast-driven bone resorption, and reduced regenerative capacity in periodontal tissues. Experimental studies suggest that Nrf2 activation can restore the redox balance and attenuate inflammation and bone destructive responses in a periodontal model. Moreover, therapeutic approaches involving phytochemicals, microbial-derived metabolites, and redox-responsive biomaterials have been reported to influence Nrf2-related signaling in experimental settings. However, the majority of the available evidence is derived from in vitro or animal studies, and the relevance of these findings to clinical periodontitis remains to be established. This review summarizes the current advances linking oxidative stress, redox signaling, cell death pathways, and bone remodeling with Nrf2 dysfunction in periodontitis and outlines the key mechanistic insights while highlighting the existing knowledge gaps.