Programmed cell death (PCD) is an essential part of organismal development and plays fundamental roles in host defense against pathogens and the maintenance of homeostasis. However, excess activation of PCD pathways has proven to be detrimental and can drive disease. Additionally, resistance to PCD can also contribute to disease development. Modulation of PCD, therefore, has great therapeutic potential in a wide range of diseases, including infectious, neurodegenerative, autoinflammatory, and metabolic diseases and cancer. Nevertheless, manipulation of cell death and inflammation for therapeutic intervention is a delicate process, highly specific to the context of the disease of interest, making the selection of the appropriate target molecule crucially important. Several PCD pathways are associated with innate immunity, including pyroptosis, apoptosis, necroptosis, and PANoptosis, which is defined as an inflammatory PCD pathway with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. All of these PCD pathways are regulated by upstream sensors and signaling cascades that assemble multimeric complexes to serve as activation platforms for downstream molecules; these sensors and signaling molecules provide attractive target points for therapeutic intervention. Here, we discuss the molecular mechanisms of innate cell death in health and disease, with a particular focus on the molecules putatively involved in the formation of the PANoptosome and the induction of inflammatory cell death. Further, we discuss the implications and feasibility of targeting these molecules to improve disease outcomes, as well as current clinical approaches.

程序性细胞死亡 (PCD) 是有机体发育的重要组成部分，在宿主防御病原体和维持体内平衡方面发挥着重要作用。然而，PCD 通路的过度激活已被证明是有害的，并可能导致疾病。此外，对 PCD 的抗性也会促进疾病的发展。因此，PCD 的调节在广泛的疾病中具有巨大的治疗潜力，包括传染性疾病、神经退行性疾病、自身炎症、代谢性疾病和癌症。然而，用于治疗干预的细胞死亡和炎症的操纵是一个微妙的过程，对感兴趣的疾病具有高度特异性，因此选择合适的靶分子至关重要。几种 PCD 途径与先天免疫相关，包括细胞焦亡、细胞凋亡、细胞坏死和 PANoptosis，它被定义为具有细胞焦亡、细胞凋亡和/或细胞坏死等关键特征的炎症 PCD 通路，不能单独由这三种 PCD 通路中的任何一个来解释。所有这些 PCD 通路都受到上游传感器和信号级联的调节，这些传感器和信号级联组装多聚体复合物作为下游分子的激活平台；这些传感器和信号分子为治疗干预提供了有吸引力的目标点。在这里，我们讨论了先天细胞死亡在健康和疾病中的分子机制，特别关注假定参与 PANoptosome 形成和炎症细胞死亡诱导的分子。此外，我们讨论了靶向这些分子以改善疾病结果的意义和可行性，