Inhibiting primary cilia formation attenuates gingival fibroblast senescence and gingival aging via the PI3K-AKT pathway

Aging, as an intrinsic risk factor, accelerates gingival inflammation and periodontal diseases. However, the cellular and molecular mechanisms driving gingival aging remain unclear, hindering the development of targeted therapies. In this study, we performed the first single-cell transcriptomic analysis of aging human gingiva, identifying primary cilia as pivotal regulators of gingival fibroblast senescence. We demonstrated that aged gingival tissues exhibit increased fibroblast senescence and enhanced cilia formation compared to young tissues. Genetic knockdown of ciliogenesis-associated genes (IFT88 and KIF3A) significantly reduced senescence markers and alleviated DNA damage in aged fibroblasts through activation of the PI3K-AKT signaling pathway. Functionally, adeno-associated virus-mediated inhibition of ciliogenesis in aged mice mitigated gingival fibroblast senescence, reduced inflammation, and diminished tissue fibrosis. These findings highlight primary cilia and the PI3K-AKT pathway as novel therapeutic targets for managing aging-related gingival diseases, providing a potential strategy to improve periodontal health in the elderly.