Necroptosis in apical periodontitis: A programmed cell death with multiple roles

Programmed cell death (PCD) has been a research focus for decades and different mechanisms of cell death, such as necroptosis, pyroptosis, ferroptosis, and cuproptosis have been discovered. Necroptosis, a form of inflammatory PCD, has gained increasing attention in recent years due to its critical role in disease progression and development. Unlike apoptosis, which is mediated by caspases and characterized by cell shrinkage and membrane blebbing, necroptosis is mediated by mixed lineage kinase domain-like protein (MLKL) and characterized by cell enlargement and plasma membrane rupture. Necroptosis can be triggered by bacterial infection, which on the one hand represents a host defense mechanism against the infection, but on the other hand can facilitate bacterial escape and worsen inflammation. Despite its importance in various diseases, a comprehensive review on the involvement and roles of necroptosis in apical periodontitis is still lacking. In this review, we tried to provide an overview of recent progresses in necroptosis research, summarized the pathways involved in apical periodontitis (AP) activation, and discussed how bacterial pathogens induce and regulated necroptosis and how necroptosis would inhibit bacteria. Furthermore, the interplay between various types of cell death in AP and the potential treatment strategy for AP by targeting necroptosis were also discussed.