RIPK3 Promotes Gingival Fibroblast Apoptosis and Periodontal Inflammatory Injury by Impairing Mitophagy.

OBJECTIVE

Periodontitis drives persistent inflammation, alveolar bone loss, mitochondrial dysfunction and fibroblast programmed cell death. Receptor-interacting protein kinase 3 (RIPK3) regulates inflammation and cell fate, while its role in modulating FUNDC1-associated mitophagy and cell death in periodontitis remains poorly defined.

METHODS

Clinical gingival tissues, a ligature-induced rat periodontitis model, and Pg.LPS-stimulated human gingival fibroblasts were used. RIPK3 function was verified via pharmacological inhibition and siRNA-mediated knockdown, combined with mitophagy intervention and detection of mitochondrial damage, apoptosis and necroptosis.

RESULTS

RIPK3 and pTyr18-FUNDC1 were upregulated while LC3-II was downregulated in periodontitis tissues. RIPK3 inhibition restored defective mitophagic flux, alleviated mitochondrial dysfunction, apoptosis and MLKL-mediated necroptosis. Mitophagy activation reversed LPS-induced injuries, whereas autophagy inhibition abrogated RIPK3-related protection. RIPK3 acts as an upstream regulator of FUNDC1 Tyr18 phosphorylation, without confirming direct catalytic activity or specific FUNDC1 dependency.

CONCLUSION

RIPK3 elevation exacerbates periodontal damage via mitophagy impairment and dual activation of apoptosis and necroptosis. RIPK3 inhibition improves mitophagy, though its direct targeting of FUNDC1 requires further validation. RIPK3 serves as a promising therapeutic candidate for periodontitis.