Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.

由专用分子机器介导的调节细胞死亡，称为程序性细胞死亡，在健康和疾病中发挥着重要作用。细胞凋亡、坏死性凋亡和焦亡是三种这样的程序性细胞死亡方式。半胱氨酸蛋白酶的半胱天冬酶家族是程序性细胞死亡的关键调节因子。在细胞凋亡过程中，caspase 的级联激活介导信号转导和细胞破坏，而当激活的 caspase 裂解 Gasdermin 时，就会发生细胞焦亡，然后 Gasdermin 可以在质膜上形成孔。坏死性凋亡是由 RIPK3 和 MLKL 介导的一种不依赖于 caspase 的程序性坏死，可通过 caspase-8 介导的 RIPK1 裂解来抑制。对细胞生存至关重要的细胞稳态机制的破坏，例如正常的离子和氧化还原平衡以及溶酶体通量，也可以在不调用程序性细胞死亡机制的情况下诱导细胞死亡。兴奋性毒性、铁死亡和溶酶体细胞死亡是此类细胞死亡模式的例子。在这篇综述中，我们概述了主要的细胞死亡机制，重点介绍了对其复杂调控和执行及其与人类疾病相关性的最新见解。