Emerging biomodels to understand the pathophysiology of sepsis and evaluate new therapeutic strategies targeting extracellular histones

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Background: Extracellular histones (extH) have emerged as key damage-associated molecular patterns (DAMPs) driving multi-organ failure in sepsis. Despite their correlation with disease severity, organ-specific mechanisms of extH toxicity and targeted therapeutic strategies remain underexplored. Main body: This review dissects extH-mediated pathophysiology across vital organs including heart, lungs, kidneys, liver, and brain, through convergent pathways including TLR activation, NLRP3 inflammasome signaling, NETosis, oxidative stress, calcium influx, pyroptosis, and microvascular thrombosis. Conventional 2D cell cultures fail to recapitulate tissue architecture, multicellular interactions, and hemodynamic forces, while rodent models exhibit poor clinical translatability due to specific immune responses and physiology. Moreover, conventional 2D models and animal models do not usually cover the heterogenicity we can find in sepsis. In contrast, advanced human-relevant 3D biomodels offer transformative advantages: organoids faithfully recreate organ-specific cellular heterogeneity and developmental gradients; 3D-bioprinted biomodels provide precise spatial control of immune-endothelial-stromal interactions within biomimetic matrices; organ-on-chip platforms integrate physiological shear stress, dynamic flow, oxygen gradients, and real-time inter-organ communication, enabling study of extH-driven neutrophil adhesion, platelet aggregation, barrier dysfunction, and cytokine storms under clinically relevant conditions. Conclusion: Next-generation 3D biomodels overcome traditional translational barriers, facilitating the comprehension of the pathophysiological mechanisms occurring in tissues during sepsis. Moreover, these advanced biomodels enable high-throughput screening of extH-neutralizing agents (e.g., heparinoids, anti-histone antibodies) and hemoperfusion technologies, thereby advancing precision intensive care medicine. By bridging mechanistic insights to clinical strategies that mitigate inflammation, endothelial dysfunction, thrombosis and long-term sequelae, these platforms promise transformative advances in sepsis management and intensive care outcomes.

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