Regulation of endoplasmic reticulum stress and ferroptosis by rutin in a rat model of periodontitis.

Abstract

Periodontitis is a bacteria-induced chronic inflammatory disease affecting tooth-supporting structures, involving endoplasmic reticulum (ER) stress and ferroptosis with a potential link between them. This study investigated the effects of rutin, a plant-derived flavonoid with diverse bioactivities, such as anti-inflammatory and antioxidant properties, on periodontitis in a rat model by modulating ER stress and ferroptosis pathways. Periodontitis was induced in rats using silk ligatures around molars. Rutin (0, 100, or 200 mg/kg) was administered orally for seven consecutive days, starting one day before ligation, with nonligated rats as controls (8 per group). Using micro-computed tomography (µCT) and histology, the damage in periodontium was evaluated, while the gingival protein expressions for pro-inflammatory cytokines, ER stress, and ferroptosis were analyzed by Western blotting. Through µCT and histological analysis, gingival inflammation and loss of tooth-supporting tissue in rats with periodontitis were confirmed. Rutin reduced these effects dose-dependently. Western blotting showed significantly elevated pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and ER stress markers (activating transcription factor 6, binding immunoglobulin protein, and C/EBP homologous protein), but reduced ferroptosis markers (solute carrier family 7 member 11 and glutathione peroxidase 4) in rats with periodontitis. Rutin dose-dependently alleviated the alterations in the above cytokines and markers. Parameters of gingival inflammation and soft/hard tissue loss correlated positively with ER stress markers and negatively with ferroptosis markers, though no correlation was found between ER stress and ferroptosis. These findings suggest rutin alleviates periodontitis by independently modulating ER stress and ferroptosis.