Circadian gene BMAL1 attenuates gingival fibroblast senescence to suppress diabetic periodontitis progression

In a hyperglycemic environment, periodontal inflammatory responses and the destruction of periodontal supporting tissues are exacerbated, leading to a severe form of diabetes periodontitis (DPD). Diabetes and periodontitis exhibit a bidirectional relationship that significantly increases the complexity and severity of each condition. A key pathological feature in this process is the functional impairment of gingival fibroblasts (GFs) within the high-glucose inflammatory microenvironment. In this study, a DPD mouse model was established. It was found that diabetes significantly aggravated alveolar bone resorption and accelerated GFs senescence, which was accompanied by a marked downregulation of brain and muscle ARNT-like 1 (BMAL1) expression. Pharmacological activation of BMAL1 effectively mitigated GFs senescence and mitochondrial dysfunction, and consequently alleviated alveolar bone destruction in DPD mice. By simulating the high-glucose inflammatory microenvironment in vitro, we confirmed that the combination of high glucose (HG) and lipopolysaccharide (LPS) activates the JAK1-STAT3 signaling pathway, downregulates BMAL1, disrupts mitochondrial homeostasis, and ultimately induces GFs senescence. This study elucidates the pathological mechanism underlying GFs senescence in the high-glucose inflammatory microenvironment, thereby providing a novel perspective for the targeted therapy of DPD.