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.

The blood-brain barrier (BBB) is a unique specialization of central nervous system (CNS) capillary endothelial cells that controls molecular traffic between the blood and the brain. In doing so, the BBB maintains a safe and homeostatic environment for proper neuronal function. The BBB restricts drug delivery to the CNS, while BBB defects contribute to neurodevelopmental and neurodegenerative disorders. In this Review, we discuss the distinct features of CNS capillary endothelial cells that form the BBB. Meanwhile, interactions between capillary endothelial cells and surrounding pericytes, astrocytes and with the extracellular matrix of the basement membrane, are crucial for BBB formation and maintenance. We examine how molecular regulators of capillary endothelial cells and signalling pathways that control cell-cell interactions render the BBB a dynamic and selective interface. We highlight emerging areas of BBB research, including heterogeneity of brain vascular permeability and technology development. Finally, we discuss how insights from BBB biology are shaping therapeutic strategies targeting the BBB.

Aminoacyl-tRNA synthetases (ARSs) are best known for their central role in translation, where they attach specific amino acids to their matching tRNAs to ensure accurate protein synthesis. However, in humans, these enzymes have evolved far beyond this textbook function. Emerging research reveals that ARSs have versatile roles in cells, acting as sensors, signalling hubs and regulators of cellular and systemic homeostasis. The structural adaptability of ARSs enables them to connect metabolic cues with gene expression, protein networks and stress responses. Disruptions in ARS functions are increasingly linked to a wide range of diseases, from cancer to neurodegeneration. In this Review, we examine how ARSs operate at the intersection of translation and signalling networks: we discuss their catalytic regulation functions, structural diversification, non-canonical functions such as in transcription and translation regulation, protein degradation and signal transduction and their disease relevance. By bringing these insights together, we offer a unified view of ARSs as multifaceted proteins and open new avenues for discoveries in molecular biology, pathophysiology and drug design.

Cells use specialized membrane extensions that enable the exchange of signals, organelles and other cargo to support long-range communication within complex tissues. Among these, tunnelling nanotubes, cytonemes and migrasomes have emerged as key contributors to development, immune responses and disease. Growing evidence has revealed that these structures are more prevalent and functionally diverse than previously appreciated, prompting a re-evaluation of how cells coordinate behaviour across space. In this Review, we discuss recent advances in understanding the formation, regulation and specificity of these dynamic connections, with an emphasis on tunnelling nanotubes and cytonemes, and highlight common principles underlying their architecture and cargo transfer. We further explore how their dysregulation contributes to pathology, underscoring the need to integrate these structures into current models of tissue organization.