Pannexin1 Inhibition Suppresses Porphyromonas gingivalis-Induced Ferroptosis in Peri-Implantitis by Regulating the NRF2/SLC7A11/GPX4 Pathway.

OBJECTIVES: Pannexin1 (Panx1), a channel-forming protein, has been implicated in multiple forms of programmed cell death. This study aimed to investigate the role and underlying molecular mechanisms of Panx1 in regulating ferroptosis during peri-implantitis (PI).

MATERIAL AND METHODS: Panx1 expression in PI patients was evaluated through bioinformatics analysis and validated using clinical samples. In vitro, Porphyromonas gingivalis-stimulated osteoblasts were assessed for changes in Panx1 and ferroptosis-related markers. After Panx1 inhibition or knockdown, cellular iron content, reactive oxygen species levels, and lipid peroxidation were measured to evaluate ferroptosis. In vivo, a mouse model of P. gingivalis-induced PI was established to evaluate the effects of pharmacological Panx1 inhibition on ferroptosis and peri-implant bone loss.

RESULTS: Bioinformatic analysis revealed that Panx1 was significantly upregulated in PI tissue. Clinical samples confirmed that Panx1 expression at both gene and protein levels was markedly elevated in PI tissues compared to healthy controls. In vitro, P. gingivalis upregulated Panx1 expression and induced ferroptosis, characterized by increased lipid peroxidation, iron overload, and ROS accumulation. Panx1 inhibition or knockdown alleviated these ferroptosis-related changes and was associated with the upregulation of the NRF2/SLC7A11/GPX4 antioxidant signaling pathway. In vivo, Panx1-inhibited PI mice significantly restored the expression of key anti-ferroptosis proteins in peri-implant tissues and markedly reduced vertical and circumferential alveolar bone loss around implants compared to untreated PI mice.

CONCLUSIONS: Panx1 inhibition suppressed P. gingivalis-induced ferroptosis in PI accompanied by the upregulation of the NRF2/SLC7A11/GPX4 antioxidant pathway. Targeting Panx1 may provide a potential therapeutic strategy for treating PI.