Extracellular histones, primarily nuclear proteins involved in chromatin organization, have emerged as key mediators in pathological processes in critically ill patients. When released into circulation due to cell death mechanisms such as NETosis, histones act as damage‐associated molecular patterns (DAMPs), contributing to excessive inflammation, endothelial dysfunction, immune response dysregulation, coagulation activation, cell death, and multi‐organ damage. Increasing evidence supports their role in the pathophysiology of sepsis, acute lung injury, cardiac injury, pancreatitis, and other life‐threatening conditions. Given their strong association with disease severity and prognosis, circulating histones have gained attention as potential clinical biomarkers for early diagnosis, prognosis, and therapeutic monitoring in critically ill patients. This review discusses the biological roles of extracellular histones, their potential as biomarkers, different approaches to measure them, and emerging therapeutic strategies aimed at neutralizing or removing circulating histones to improve patient outcomes in severe medical conditions. Impact statement: This review highlights extracellular histones as key mediators and biomarkers in sepsis, proposing their use in diagnosis, prognosis, and treatment monitoring. Integrating quantitative proteomics for the detection of circulating histones may enhance patient stratification and guide therapeutic strategies, advancing personalized medicine in critical care.

Disseminated Intravascular Coagulation (DIC) is a type of tissue and organ dysregulation in sepsis, due mainly to the effect of the inflammation on the coagulation system. Unfortunately, the underlying molecular mechanisms that lead to this disorder are not fully understood. Moreover, current biomarkers for DIC, including biological and clinical parameters, generally provide a poor diagnosis and prognosis. In recent years, non-coding RNAs have been studied as promising and robust biomarkers for a variety of diseases. Thus, their potential in the diagnosis and prognosis of DIC should be further studied. Specifically, the relationship between the coagulation cascade and non-coding RNAs should be established. In this review, microRNAs, long non-coding RNAs, and circular RNAs are studied in relation to DIC. Specifically, the axis between these non-coding RNAs and the corresponding affected pathway has been identified, including inflammation, alteration of the coagulation cascade, and endothelial damage. The main affected pathway identified is PI3K/AKT/mTOR axis, where several ncRNAs participate in its regulation, including miR-122-5p which is sponged by circ_0005963, ciRS-122, and circPTN, and miR-19a-3p which is modulated by circ_0000096 and circ_0063425. Additionally, both miR-223 and miR-24 were found to affect the PI3K/AKT pathway and were regulated by lncGAS5 and lncKCNQ1OT1, respectively. Thus, this work provides a useful pipeline of inter-connected ncRNAs that future research on their impact on DIC can further explore.

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. 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. 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.