Multiple organ dysfunction syndrome: molecular mechanisms and therapeutic strategies

Figures

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  Fig. 1. Schematic diagram of MODS. a Core framework of MODS management. Etiology is classified into infectious causes and noninfectious triggers, such as trauma and shock. The mechanism encompasses pathological processes, including dysregulated inflammation, programmed cell death, mitochondrial dysfunction, and microcirculatory disturbance. Diagnosis and assessment involve scoring systems such as SOFA and APACHE II, along with biomarkers for risk stratification. Therapy comprises strategies covering primary disease treatment, organ support, mechanical ventilation, metabolic regulation, and targeted temperature management. b Challenges in MODS research and clinical practice. This section underscores the limitations throughout the framework. Etiology is complicated by patient heterogeneity. Mechanistic studies face challenges such as complex pathogenesis and discrepancies between animal and human models. Diagnosis suffers from an overabundance of indicators and low rapid detection rates. Therapy is constrained by limited efficacy of targeted treatments and poor clinical translation of research findings. c AI-powered bench-to-bedside solution for MODS. Bench side (research end): Serves as…

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  Fig. 2. Inflammation disorders in MODS. a Local inflammatory response. In the initial stages of inflammation, DAMPs and PAMPs recruit inflammatory cells to the damaged tissue, thereby initiating a localized inflammatory reaction. The recruited inflammatory cells subsequently secrete inflammatory cytokines and ROS, further amplifying the response by attracting more cells to the damaged tissue. b Systemic inflammatory response: When disease persists or new pathogens arise, inflammatory cell-factor interactions intensify, activating more cells and amplifying the inflammatory cascade. TNF-α and IL-1 activate pathways (NF-κB, MAPK, PI3K/AKT), which promote the expression of inflammatory and adhesion molecule genes. Additionally, inflammation triggers coagulation, forming microthrombi that activate more cells and release mediators, exacerbating tissue damage in a vicious inflammation-coagulation cycle. c Inflammation and MODS: The systemic inflammatory response leads to multiple organ dysfunction by promoting coagulation abnormalities, degrading the extracellular matrix and directly activating PRR-related signaling pathways through humoral mediators, which results in tissue cell damage.…

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  Fig. 3. Pattern recognition receptor-mediated signal transduction. In different disease states, PAMPs and DAMPs are recognized by specific receptors on cell membranes and inside cells. With the assistance of accessory proteins, these molecules transmit signals into the cell, triggering various biological responses. The key signaling pathways involved in MODS include the following: (1) cGAS/STING (2) IL-1/NF-κB and IL-1/MAPK (3) IL-6/NF-κB, IL-6/MAPK (4) TNF-α/NF-κB, TNF-α/MAPK (5) Ang-1/Tie2 (6) NLR/inflammasome activation (7) eATP/P2X7 (8) HMGB1/RAGE/NF-κB (9) LPS/C5R (10) TLRs/MyD88/NF-κB (11) LPS/CLEC5A/CXCL5 and LPS/CLEC5A/ICAM-1. Created in BioRender. xu, x. (2026) https://BioRender.com/8gxfk7p

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  Fig. 4. The mechanism of coagulation dysfunction in MODS. Endothelial injury, including glycocalyx injury or degradation, triggers the activation of the intrinsic coagulation pathway. The TF released from activated monocytes and injured vascular endothelium initiates the extrinsic coagulation cascade. These two pathways ultimately convert fibrinogen to fibrin, resulting in the formation of fibrin clots. Platelets, activated under various conditions, bind to these fibrin clots to form thrombosis. Activated platelets also release different types of granules that promote thrombosis and inflammation. The STING/STXBP2 and STING/NLRP3 pathways are involved in the activation and granule release of platelets. Normally, PAI regulates the conversion of plasminogen to plasmin and its suppression by PAMPs during sepsis. The extensive consumption of platelets and clotting factors mediates the occurrence of DIC and hemorrhage. Ultimately, the combined effects of DIC and thrombosis mediate the development of MODS. Created in BioRender. xu, x. (2026) https://BioRender.com/undefined

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  Fig. 5. Molecular mechanism of regulated cell death in MODS. a Necroptosis. Traditional necroptosis molecules, including RIPK1, RIPK3 and MLKL, undergo phosphorylation that enhances their function, while ubiquitination diminishes necroptosis. In atypical necroptosis pathways, the oxidation or phosphorylation of CaMKII and HSP1/ZBP1 directly activates RIPK3. b Apoptosis. These pathways include death receptor-mediated, mitochondria-mediated and ER-mediated apoptosis signaling pathways. cFerroptosis. The core mechanism of ferroptosis involves iron overload, lipid peroxidation and impaired antioxidation. Lipid peroxidation of the cell membrane leads to cell rupture and subsequent cell death. TF/TFR and NCOA4/SENP2-mediated ferritinophagy signaling pathways are implicated in the pathogenesis of iron overload. GPX4 and CoQ10 are key antioxidant molecules. ACSL4 is responsible for driving lipid peroxidation. d Pyroptosis. The NLRP3-related inflammasome plays a key role by inducing the activation of pro-caspase 1, which promotes a type of cell death called pyroptosis. Additionally, pro-caspase 4, 5 and 11 can be activated independently of the inflammasome. Both of these mechanisms can lead to…

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  Fig. 6. Novel intervention therapeutic strategies for organ injury. New types of therapy reagents that target DAMPs, PRRs, RCD molecules (regulated cell death molecules), inflammation factors, and coagulation factors are involved in the treatment. Nanomaterials, hydrogels and other materials, through their unique molecular properties, can release drugs in a targeted manner into specific organs or at the molecular and organelle levels, thereby alleviating the pathological process caused by different etiologies of organ injuries. Created in BioRender. xu, x. (2026) https://BioRender.com/x5gm0f8