Regulated cell death in sepsis: reframing NETosis within the spectrum of apoptosis and inflammatory lytic death

Sepsis is characterized by dysregulated inflammation leading to organ dysfunction. While immune activation and metabolic stress are central features, accumulating evidence suggests that regulated cell death programs actively influence inflammatory trajectories rather than serving as passive end-stage events. Apoptosis, pyroptosis, necroptosis, ferroptosis, and neutrophil extracellular trap (NET) formation have each been implicated in sepsis; however, their relative hierarchy, temporal dynamics, and compartment-specific relevance remain incompletely defined.

To synthesize current evidence on regulated cell death pathways in sepsis and to propose a phase-specific and compartment-oriented framework that integrates apoptotic, inflammatory lytic, and NET-associated mechanisms within a unified inflammatory model.

A narrative review of experimental, translational, and clinical studies examining apoptosis, pyroptosis, necroptosis, ferroptosis, PANoptosis, and NETosis in sepsis and related inflammatory states was conducted. Emphasis was placed on signaling dependency, inflammatory consequences, temporal phase distinctions, and cellular compartment heterogeneity.

Apoptosis remains the dominant leukocyte death program associated with late-phase immune depletion and immunosuppression. In contrast, inflammasome-mediated pyroptosis and RIPK1/RIPK3-dependent necroptosis amplify early hyperinflammatory responses by inducing membrane permeabilization and damage-associated molecular pattern release. Ferroptosis represents an emerging iron-dependent metabolic-inflammatory interface with potential organ-specific relevance, although clinical validation remains limited. NET formation, often interpreted as a distinct death program, is more appropriately understood as a context-dependent effector mechanism linking innate immunity to thromboinflammation rather than representing the predominant terminal fate of leukocytes in sepsis. Increasing evidence supports pathway crosstalk and PANoptotic integration, suggesting that regulated cell death programs function as overlapping inflammatory networks rather than isolated processes.