Restoring Cellular Homeostasis as a Therapeutic Strategy for Periodontitis

Periodontitis is a chronic inflammatory disease characterized by persistent inflammation, redox imbalance, and mitochondrial dysfunction, leading to progressive impairment of periodontal cellular function and tissue integrity. Current periodontal therapies primarily focus on controlling inflammation and promoting tissue regeneration. However, these approaches do not adequately restore the function of resident cells compromised by an inflammatory microenvironment. Restoration of cellular homeostasis prior to inducing regeneration may enhance treatment outcomes for effective periodontal repair. This study aimed to investigate the role of CPNE7 in periodontal homeostasis and to evaluate whether selcopintide (SCPT), a CPNE7-derived peptide, restores cellular function under inflammatory periodontal conditions and exerts therapeutic effects in a mouse ligature-induced periodontitis model. In aged periodontal tissues, CPNE7 expression was reduced, accompanied by increased oxidative stress and decreased Nrf2 expression. Cpne7 knockout mice also exhibited periodontal structural abnormalities and showed aggravated alveolar bone loss and inflammatory responses following periodontitis induction. SCPT reduced excessive reactive oxygen species accumulation induced by inflammatory stimuli and restored redox balance, thereby supporting cellular homeostasis. In addition, SCPT improved mitochondrial function under inflammatory conditions, as evidenced by restored mitochondrial morphology and bioenergetic function, while attenuating inflammatory signaling and apoptosis. These protective effects were associated with activation of the Nrf2 antioxidant pathway. Importantly, topical administration of SCPT significantly attenuated periodontal destruction and alveolar bone loss in the ligature-induced periodontitis model, demonstrating its therapeutic efficacy in vivo. Collectively, these findings indicate that CPNE7 is an important contributor to periodontal tissue homeostasis and that SCPT restores redox balance, mitochondrial function, and inflammatory stability, highlighting CPNE7-derived peptides as a promising therapeutic strategy for periodontitis.