Metformin switches cell death modes to soothe the apical periodontitis via ZBP1

Abstract Apical periodontitis (AP) is a disease caused by pathogenic microorganisms and featured with the degradation of periapical hard tissue. Our recent research showed the crucial role of Z‐DNA binding protein 1 (ZBP1)‐mediated necroptosis and apoptosis in the pathogenesis of AP. However, the specific regulatory mechanisms of ZBP1 in AP are not fully elucidated. It was found that metformin has a regulatory role in cell necroptosis and apoptosis. But whether and how metformin regulates necroptosis and apoptosis through the ZBP1 in the context of AP remains unknown. This study provided evidence that lipopolysaccharide (LPS) promotes the synthesis of left‐handed Z‐nucleic acids (Z‐NA), which in turn activates ZBP1. Knockout of Zbp1 by CRISPR/Cas9 technology significantly reduced LPS‐induced necroptosis and apoptosis in vitro. By using Zbp1 ‐knockout mice, periapical bone destruction was alleviated. Moreover, type I interferon induced the expression of interferon‐stimulated genes (ISGs), which serve as a major source of Z‐NA. In addition, the RNA‐editing enzyme Adenosine Deaminase RNA specific 1 (ADAR1) prevented the accumulation of endogenous Z‐NA. Meanwhile, metformin suppressed the ZBP1‐mediated necroptosis by inhibiting the expression of ZBP1 and the accumulation of ISGs. Metformin also promoted mitochondrial apoptosis, which is critical for the elimination of intracellular bacterial infection. The enhanced apoptosis further promoted the healing of infected apical bone tissues. In summary, these results demonstrated that the recognition of Z‐NA by ZBP1 plays an important role in AP pathogenesis. Metformin suppressed ZBP1‐mediated necroptosis and promoted apoptosis, thereby contributing to the soothing of inflammation and bone healing in AP.