Mechanisms, regulation and clinical relevance of necroptosis

Necroptosis is a programmed lytic cell death pathway executed through mixed lineage kinase domain-like protein (MLKL)-driven plasma membrane disruption and has pivotal roles in both health and disease. Recent advances have led us to propose the classification of mammalian necroptosis into two subtypes: extrinsic and intrinsic necroptosis, which differ in their mechanisms of trigger sensing and signal integration. Extrinsic necroptosis is initiated by membrane-bound receptors, including cell-surface receptors such as tumour necrosis factor receptor 1 (TNFR1) and Toll-like receptor 4 (TLR4), as well as endosomal receptors such as TLR3, whereas intrinsic necroptosis is initiated intracellularly through sensors such as Z-DNA-binding protein 1 (ZBP1) detecting cytosolic Z-nucleic acids. In this Review, we provide an overview of the molecular mechanisms of necroptosis, highlighting the latest insights into their complex regulatory networks, execution pathways, and the growing clinical relevance and therapeutic potential of targeting necroptosis in human diseases.