Cell death crosstalk in NET-Driven inflammation: mechanisms, disease contexts, and therapeutic perspectives

Neutrophil extracellular traps (NETs) are chromatin-based extracellular structures consisting of DNA, histones and multiple antimicrobial proteins, which exert dual biological effects in host defense and inflammation-triggered tissue injury. This review focuses on NET-associated signaling pathways and their regulatory crosstalk with diverse forms of regulated cell death (RCD) in inflammatory disorders. First, we summarize the structural characteristics and biogenesis pathways of NETs closely linked to inflammatory amplification, including lytic and non-lytic NETosis as well as reactive oxygen species (ROS)-dependent and ROS-independent mechanisms, and elaborate the functions of NADPH oxidase, myeloperoxidase, neutrophil elastase, peptidylarginine deiminase 4 and gasdermin D during these processes. Second, we discuss how NET-derived damage-associated molecular patterns, such as DNA, histones, granular proteases, ROS and mitochondrial DNA, interact with apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy and cuproptosis. Under pathological conditions, excessive NET formation or impaired NET clearance leads to autoantigen exposure, accelerated thrombosis, enhanced inflammasome activation, parenchymal cell damage and modulated tumor progression. Finally, we outline therapeutic interventions targeting NET biogenesis, NET clearance and downstream NETs-driven signaling, with an emphasis on the translational potential and safety concerns of these strategies across distinct diseases. Future investigations are required to decipher context-dependent NETs-RCD regulatory circuits, standardize NETs detection protocols, and develop precision-targeted therapeutics that restrain pathological inflammation while preserving host antimicrobial defense.