BMAL1 downregulation drives PANoptosis and the osteogenic differentiation impairment of PDLSCs by ERK/AP‐1 signaling pathway

Periodontitis is a chronic inflammatory condition of the oral cavity marked by the destruction of periodontal attachment and resorption of alveolar bone. One strategy to delay alveolar bone loss in periodontitis involves maintaining the osteogenic differentiation function of periodontal ligament stem cells (PDLSCs). The circadian rhythm influences the fate of mesenchymal stem cells, with the core circadian gene BMAL1 playing a crucial role in regulating pyroptosis, apoptosis, and necroptosis. PANoptosis is a novel form of programmed cell death, encompassing pyroptosis, apoptosis, and necroptosis, which may play a role in regulating the osteogenic activity of PDLSCs. Our study aims to detect the role of PANoptosis of PDLSCs in periodontitis and elucidate the underlying relationship between BMAL1 and PANoptosis. We found that treatment with lipopolysaccharide leads to the downregulation of BMAL1 expression, which subsequently induces RIPK1-PANoptosome-mediated PANoptosis in PDLSCs, impairing their osteogenic differentiation function. Notably, inhibition of the RIPK1-PANoptosome improved the expression of osteogenic differentiation-related genes and proteins. Mechanistic exploration revealed that BMAL1 downregulation induces PANoptosis in PDLSCs through the ERK/AP-1 signaling pathway. This study highlights the potential therapeutic targets for mitigating bone loss in periodontitis.