Stoess Christian, Leszczynska Aleksandra, Kui Lin, Feldstein Ariel E
Department of Pediatric Gastroenterology, University of California, San Diego, San Diego, CA, United States.
Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Front Cell Dev Biol. 2023 Aug 17;11:1218807. doi: 10.3389/fcell.2023.1218807. eCollection 2023.
In recent years, there has been a rapid expansion in our understanding of regulated cell death, leading to the discovery of novel mechanisms that govern diverse cell death pathways. One recently discovered type of cell death is pyroptosis, initially identified in the 1990s as a caspase-1-dependent lytic cell death. However, further investigations have redefined pyroptosis as a regulated cell death that relies on the activation of pore-forming proteins, particularly the gasdermin family. Among the key regulators of pyroptosis is the inflammasome sensor NOD-like receptor 3 (NLRP3), a critical innate immune sensor responsible for regulating the activation of caspase-1 and gasdermin D. A deeper understanding of pyroptosis and its interplay with other forms of regulated cell death is emerging, shedding light on a complex regulatory network controlling pore-forming proteins and cell fate. Cell death processes play a central role in diseases such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, autoinflammatory disorders, and cancer. Cell death often acts as a starting point in these diseases, making it an appealing target for drug development. Yet, the complete molecular mechanisms are not fully understood, and new discoveries reveal promising novel avenues for therapeutic interventions. In this review, we summarize recent evidence on pathways and proteins controlling pyroptosis and gasdermins. Furthermore, we will address the role of pyroptosis and the gasdermin family in metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Additionally, we highlight new potential therapeutic targets for treating metabolic dysfunction-associated steatohepatitis and other inflammatory-associated diseases.
近年来，我们对程序性细胞死亡的理解迅速扩展，从而发现了控制多种细胞死亡途径的新机制。最近发现的一种细胞死亡类型是焦亡，它最初在20世纪90年代被确定为一种依赖半胱天冬酶-1的溶解性细胞死亡。然而，进一步的研究将焦亡重新定义为一种依赖于成孔蛋白激活的程序性细胞死亡，尤其是gasdermin家族。焦亡的关键调节因子之一是炎性小体传感器NOD样受体3（NLRP3），它是一种关键的固有免疫传感器，负责调节半胱天冬酶-1和gasdermin D的激活。对焦亡及其与其他形式的程序性细胞死亡之间相互作用的更深入理解正在浮现，这为控制成孔蛋白和细胞命运的复杂调节网络提供了线索。细胞死亡过程在诸如代谢功能障碍相关脂肪性肝病、代谢功能障碍相关脂肪性肝炎、自身炎症性疾病和癌症等疾病中起着核心作用。细胞死亡往往是这些疾病的起始点，使其成为药物开发的一个有吸引力的靶点。然而，完整的分子机制尚未完全了解，新的发现揭示了有前景的治疗干预新途径。在这篇综述中，我们总结了关于控制焦亡和gasdermin的途径及蛋白质的最新证据。此外，我们将探讨焦亡和gasdermin家族在代谢功能障碍相关脂肪性肝病和脂肪性肝炎中的作用。此外，我们强调了治疗代谢功能障碍相关脂肪性肝炎和其他炎症相关疾病的新的潜在治疗靶点。
