Circadian rhythm disruption aggravates periodontitis by promoting M1 polarization via BMAL1 / IGF-1 signaling axis

Epidemiological studies have shown that disrupted circadian rhythms are associated with a higher incidence of periodontitis, but the underlying molecular mechanisms remain unclear. This study aimed to investigate the role of the core circadian clock gene brain and muscle ARNT-like 1 (BMAL1) in periodontitis progression and its potential mechanisms. Clinical periodontal tissue samples were analyzed to evaluate clock gene expression in periodontitis. Animal models of circadian rhythm disruption and BMAL1 deficiency were established to examine the effects of circadian dysregulation and BMAL1 loss on periodontal inflammation and macrophage polarization. In vitro macrophage experiments were performed to investigate the regulatory role of BMAL1 and the involvement of insulin-like growth factor 1 (IGF-1). Finally, the therapeutic effect of pharmacological BMAL1 restoration was evaluated in an experimental periodontitis model. Human periodontitis tissue samples showed impaired expression of clock genes, and the animal model showed that disrupted circadian rhythm exacerbated periodontitis. BMAL1 deficiency in experimental periodontitis resulted in more severe periodontal destruction and higher M1/M2 macrophage ratios. In vitro experiments demonstrated that BMAL1 directly bound to the insulin-like growth factor 1 (IGF-1) promoter region and promoted IGF-1 transcription, thereby contributing to the regulation of macrophage polarization. BMAL1 restoration reduced periodontal inflammation in experimental periodontitis. Circadian rhythm disruption was associated with increased M1 macrophage polarization and aggravated periodontitis. The BMAL1/IGF-1 axis may contribute to macrophage-related inflammatory regulation in periodontitis. These findings suggest that targeting the periodontal circadian clock may represent a potential strategy for attenuating periodontal inflammation.