陆军军医大学第一附属医院临床医学研究中心,重庆 400038
Received:24 November 2025,
Revised:2026-04-13,
Accepted:16 April 2026,
Published:28 June 2026
移动端阅览
鲁永玲,刘鑫.脓毒症细胞因子风暴的代谢免疫调控研究进展[J].重庆医科大学学报,2026,51(6):770-779.
Lu Yongling,Liu Xin.Research advances in immunometabolic regulation of cytokine storm in sepsis[J].Journal of Chongqing Medical University,2026,51(6):770-779.
鲁永玲,刘鑫.脓毒症细胞因子风暴的代谢免疫调控研究进展[J].重庆医科大学学报,2026,51(6):770-779. DOI: 10.13406/j.cnki.cyxb.004101.
Lu Yongling,Liu Xin.Research advances in immunometabolic regulation of cytokine storm in sepsis[J].Journal of Chongqing Medical University,2026,51(6):770-779. DOI: 10.13406/j.cnki.cyxb.004101.
脓毒症是由感染引起的宿主反应失调导致的危及生命的器官功能障碍,其早期主要表现为天然免疫细胞过度活化介导的细胞因子风暴,是导致组织损伤与器官功能障碍的核心病理生理机制。近年研究表明,免疫代谢重编程在脓毒症失控性炎症反应和细胞因子风暴的发生发展中发挥关键作用。本文在介绍脓毒症细胞因子风暴特征与机制的基础上,总结脓毒症细胞因子风暴阶段天然免疫细胞代谢重编程特征及机制、代谢重塑与炎症放大的交互节点、代谢与脓毒症脏器损伤的关系以及靶向代谢关键节点的诊疗价值等研究进展,为基于代谢免疫调控的脓毒症精准干预研究提供参考。
Sepsis refers to life-threatening organ dysfunction resulting from dysregulated host response to infection,with the main early manifestation of cytokine storm mediated by hyperactivated innate immune cells,which is a core pathophysiological mechanism for tissue injury and organ failure. Recent studies have shown that immunometabolic reprogramming plays a crucial role in the development and progression of uncontrolled inflammation and cytokine storm in sepsis. This article introduces the features and mechanisms of cytokine storm in sepsis and summarizes the research advances in the characteristics and mechanisms of metabolic reprogramming of innate immune cells during cytokine storm,the dynamic interplay between metabolic remodeling and inflammatory cascades,the association between metabolism and sepsis-induced organ damage,and the potential diagnostic and therapeutic implications of targeting critical metabolic nodes,in order to provide a reference for developing precise intervention strategies for sepsis based on immunometabolic regulation.
Singer M , Deutschman CS , Seymour CW , et al . The third international consensus definitions for sepsis and septic shock(sepsis-3) [J ] . JAMA , 2016 , 315 ( 8 ): 801 .
Schlapbach LJ , Watson RS , Sorce LR , et al . International consensus criteria for pediatric sepsis and septic shock [J ] . JAMA , 2024 , 331 ( 8 ): 665 - 674 .
Rudd KE , Johnson SC , Agesa KM , et al . Global,regional,and national sepsis incidence and mortality,1990-2017:analysis for the Global Burden of Disease Study [J ] . Lancet , 2020 , 395 ( 10219 ): 200 - 211 .
Gbd GSC . Global,regional,and national sepsis incidence and mortality,1990-2021:a systematic analysis [J ] . Lancet Glob Health , 2025 , 13 ( 12 ): 2013 - 2026 .
王伊帆 , 陈 燕 , 彭劲民 , 等 . 中国脓毒症流行病学的研究进展 [J ] . 中华重症医学电子杂志 , 2023 , 9 ( 1 ): 89 - 94 .
Wang YF , Chen Y , Peng JM , et al . Epidemiology of sepsis in China [J ] . Chin J Crit Care Intensive Care Med Electron Ed , 2023 , 9 ( 1 ): 89 - 94 .
Meyer NJ , Prescott HC . Sepsis and septic shock [J ] . N Engl J Med , 2024 , 391 ( 22 ): 2133 - 2146 .
You WB . Roles of cytokine storm in sepsis progression:biomarkers,and emerging therapeutic strategies [J ] . Front Immunol , 2025 , 16 : 1696366 .
陈仲毅 , 胡时强 , 刘德伍 , 等 . 严重烧伤感染与细胞因子风暴的研究进展 [J ] . 中华烧伤与创面修复杂志 , 2023 , 39 ( 4 ): 391 - 395 .
Chen ZY , Hu SQ , Liu DW , et al . Research advances on severe burn infection and cytokine storm [J ] . Chin J Burns , 2023 , 39 ( 4 ): 391 - 395 .
Willmann K , Moita LF . Physiologic disruption and metabolic reprogramming in infection and sepsis [J ] . Cell Metab , 2024 , 36 ( 5 ): 927 - 946 .
Jarczak D , Nierhaus A . Cytokine storm:definition,causes,and implications [J ] . Int J Mol Sci , 2022 , 23 ( 19 ): 11740 .
姚咏明 , 张 卉 , 董 宁 . 脓毒症分型:精准治疗之基石 [J ] . 中华烧伤与创面修复杂志 , 2024 , 40 ( 10 ): 915 - 919 .
Yao YM , Zhang H , Dong N . Classification of sepsis:the cornerstone for precise treatment [J ] . Chin J Burns , 2024 , 40 ( 10 ): 915 - 919 .
Nedeva C . Inflammation and cell death of the innate and adaptive immune system during sepsis [J ] . Biomolecules , 2021 , 11 ( 7 ): 1011 .
孙炳伟 , 王逸凡 , 杨云稀 . 中性粒细胞与烧伤脓毒症 [J ] . 中华烧伤与创面修复杂志 , 2024 ( 7 ): 618 - 624 .
Sun BW , Wang YF , Yang YX . Neutrophil and burn sepsis [J ] . Chin J Burns Wounds , 2024 ( 7 ): 618 - 624 .
Wu QQ , Qi SY , Kang ZF , et al . PANoptosis in sepsis:a central role and emerging therapeutic target [J ] . J Inflamm Res , 2025 , 18 : 6245 - 6261 .
Fitzpatrick SF . Immunometabolism and sepsis:a role for HIF? [J ] . Front Mol Biosci , 2019 , 6 : 85 .
Wang A , Luan HH , Medzhitov R . An evolutionary perspective on immunometabolism [J ] . Science , 2019 , 363 ( 6423 ): eaar3932 .
Ming SQ , Li XY , Xiao Q , et al . TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis [J ] . J Clin Investig , 2025 , 135 : e159400 .
Zhang YL , Wu FF , Li Y , et al . SREBF1 mediates immunoparalysis of dendritic cells in sepsis by regulating lipid metabolism and endoplasmic reticulum stress [J ] . Cell Commun Signal , 2025 , 23 ( 1 ): 286 .
Chen Q , Liang X , Wu TZ , et al . Integrative analysis of metabolomics and proteomics reveals amino acid metabolism disorder in sepsis [J ] . J Transl Med , 2022 , 20 ( 1 ): 123 .
Krupa A , Krupa MM , Pawlak K . Kynurenine pathway-an underestimated factor modulating innate immunity in sepsis-induced acute kidney injury? [J ] . Cells , 2022 , 11 ( 16 ): 2604 .
Karadima E , Chavakis T , Alexaki VI . Arginine metabolism in myeloid cells in health and disease [J ] . Semin Immunopathol , 2025 , 47 ( 1 ): 11 .
Cheng SL , Li YF , Sun XL , et al . The impact of glucose metabolism on inflammatory processes in sepsis-induced acute lung injury [J ] . Front Immunol , 2024 , 15 : 1508985 .
Pan TT , Sun SQ , Chen Y , et al . Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis [J ] . Crit Care , 2022 , 26 ( 1 ): 29 .
Liu DD , Xiao M , Zhou J , et al . PFKFB3 promotes sepsis-induced acute lung injury by enhancing NET formation by CXCR4hi neutrophils [J ] . Int Immunopharmacol , 2023 , 123 : 110737 .
Cichon I , Ortmann W , Kolaczkowska E . Metabolic pathways involved in formation of spontaneous and lipopolysaccharide-induced neutrophil extracellular traps (NETs) differ in obesity and systemic inflammation [J ] . Int J Mol Sci , 2021 , 22 ( 14 ): 7718 .
Lin ZQ , Chen D , Zhang PD , et al . Multi-omics reveal neutrophil heterogeneity in sepsis(Review) [J ] . Int J Mol Med , 2025 , 56 ( 6 ): 1 - 15 .
Kelly B , O’Neill LA . Metabolic reprogramming in macrophages and dendritic cells in innate immunity [J ] . Cell Res , 2015 , 25 ( 7 ): 771 - 784 .
Liu J , Zhang XM , Chen K , et al . CCR7 chemokine receptor-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF-1α-mediated glycolysis [J ] . Immunity , 2019 , 50 ( 3 ): 600 - 615 .
Vaupel P , Multhoff G . Revisiting the Warburg effect:historical dogma versus current understanding [J ] . J Physiol , 2021 , 599 ( 6 ): 1745 - 1757 .
Hsu CG , Li WJ , Sowden M , et al . Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages [J ] . Cell Mol Immunol , 2023 , 20 ( 2 ): 131 - 142 .
Gauthier T , Yao C , Dowdy T , et al . TGF-β uncouples glycolysis and inflammation in macrophages and controls survival during sepsis [J ] . Sci Signal , 2023 , 16 ( 797 ): eade0385 .
Li RQ , Li XQ , Zhao J , et al . Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation [J ] . Theranostics , 2022 , 12 ( 2 ): 976 - 998 .
Heieis GA , Patente TA , Almeida L , et al . Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection [J ] . Nat Commun , 2023 , 14 : 5627 .
Stienstra R , Netea-Maier RT , Riksen NP , et al . Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune responses [J ] . Cell Metab , 2017 , 26 ( 1 ): 142 - 156 .
Lachmandas E , Boutens L , Ratter JM , et al . Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes [J ] . Nat Microbiol , 2016 , 2 : 16246 .
Zhang K , Jagannath C . Crosstalk between metabolism and epigenetics during macrophage polarization [J ] . Epigenetics Chromatin . 2025 , 18 ( 1 ): 16 .
Lu J , Hou Y , Liu SX , et al . Acetyl-CoA synthetase 2 induces pyroptosis and inflammation of renal epithelial tubular cells in sepsis-induced acute kidney injury by upregulating the KLF5/NF-κB pathway [J ] . Cell Commun Signal , 2024 , 22 ( 1 ): 187 .
Kuang XD , Niu ZL , Huang ZY , et al . GDF15 attenuates sepsis-induced acute lung injury by suppressing the HIF-1α/LDHA pathway [J ] . Int Immunopharmacol , 2025 , 163 : 115198 .
Huang ZY , Teng WB , Yao LX , et al . mTOR signaling pathway regulation HIF-1 α effects on LPS induced intestinal mucosal epithelial model damage [J ] . BMC Mol Cell Biol , 2024 , 25 ( 1 ): 13 .
Kanmani S , Song XM , Kanmani P , et al . Enhancement of autophagy in macrophages via the p120-catenin-mediated mTOR signaling pathway [J ] . J Immunol , 2024 , 212 ( 1 Suppl ): S1314 - 1363 .
Guo N , Xia Y , He NN , et al . IRGM inhibits the AKT/mTOR signaling pathway by interacting with TRIM21 to alleviate sepsis-induced acute lung injury [J ] . Inflammation , 2025 , 48 ( 5 ): 3282 - 3299 .
Fu Y , Xiang Y , Zha J , et al . Enhanced STAT3/PIK3R1/mTOR signaling triggers tubular cell inflammation and apoptosis in septic-induced acute kidney injury:implications for therapeutic intervention [J ] . Clin Sci , 2024 , 138 ( 6 ): 351 - 369 .
Fu XZ , Wang Y . Correction to:Interferon-γ regulates immunosuppression in septic mice by promoting the Warburg effect through the PI3K/AKT/mTOR pathway [J ] . Mol Med , 2023 , 29 ( 1 ): 110 .
Huang J , Liu K , Zhu S , et al . AMPK regulates immunometabolism in sepsis [J ] . Brain Behav Immun , 2018 , 72 : 89 - 100 .
Chen HT , Du PP , Guo R , et al . Artesunate mitigates sepsis-induced acute kidney injury via lactate/AMPK/mTOR-regulated autophagy based on multi-omics [J ] . Drug Des Dev Ther , 2025 , 19 : 5911 - 5928 .
Richter RP , Ashtekar AR , Zheng L , et al . Glycocalyx heparan sulfate cleavage promotes endothelial cell angiopoietin-2 expression by impairing shear stress-related AMPK/FoxO1 signaling [J ] . JCI Insight , 2022 , 7 ( 15 ): e155010 .
Xu YH , Zhu Y , Shi Y , et al . Immune checkpoint VISTA negatively regulates microglia glycolysis and activation via TRIM28-mediated ubiquitination of HK2 in sepsis-associated encephalopathy [J ] . Mol Neurobiol , 2025 , 62 ( 4 ): 4452 - 4465 .
Yuan Y , Fan GJ , Liu YQ , et al . The transcription factor KLF14 regulates macrophage glycolysis and immune function by inhibiting HK2 in sepsis [J ] . Cell Mol Immunol , 2022 , 19 ( 4 ): 504 - 515 .
Jing GQ , Gong HL , Wang H , et al . OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis [J ] . J Neuroinflammation , 2025 , 22 ( 1 ): 154 .
Liu ZJ , Le YF , Chen H , et al . Role of PKM2-mediated immunometabolic reprogramming on development of cytokine storm [J ] . Front Immunol , 2021 , 12 : 748573 .
Zhang Q , Luo P , Xia F , et al . Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis [J ] . Cell Chem Biol , 2022 , 29 ( 8 ): 1248 - 1259 .
Shi X , Zhou HP , Wei J , et al . The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases [J ] . Redox Biol , 2022 , 58 : 102553 .
Ma ZM , Wu YX , Rao ZB , et al . PGK1 phosphorylates NLRP3 and mediates inflammasome activation independent of its glycolytic activity [J ] . Cell Rep , 2025 , 44 ( 6 ): 115785 .
Atallah R , Gindlhuber J , Heinemann A . Succinate in innate immunity:linking metabolic reprogramming to immune modulation [J ] . Front Immunol , 2025 , 16 : 1661948 .
Fu J , Han ZY , Wu ZB , et al . GABA regulates IL-1β production in macrophages [J ] . Cell Rep , 2022 , 41 ( 10 ): 111770 .
Llibre A , Kucuk S , Gope A , et al . Lactate:A key regulator of the immune response [J ] . Immunity , 2025 , 58 ( 3 ): 535 - 554 .
Qiao J , Tan Y , Liu HC , et al . Histone H3K18 and ezrin lactylation promote renal dysfunction in sepsis-associated acute kidney injury [J ] . Adv Sci , 2024 , 11 ( 28 ): 2307216 .
Lu ZQ , Fang P , Li S , et al . Lactylation of histone H3k18 and Egr1 promotes endothelial glycocalyx degradation in sepsis-induced acute lung injury [J ] . Adv Sci , 2025 , 12 ( 7 ): 2407064 .
Peace CG , O’Neill LAJ . The role of itaconate in host defense and inflammation [J ] . J Clin Investig , 2022 , 132 ( 2 ): e148548 .
Li WZ , Li YG , Kang JQ , et al . 4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING [J ] . Cell Rep , 2023 , 42 ( 3 ): 112145 .
Wu KK , Xu XF , Wu MY , et al . MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice [J ] . Nat Commun , 2024 , 15 : 8624 .
Zhang H , Wang Y , Qu MD , et al . Neutrophil,neutrophil extracellular traps and endothelial cell dysfunction in sepsis [J ] . Clin Transl Med , 2023 , 13 ( 1 ): e1170 .
Smart L , MacDonald SPJ , Burrows S , et al . Endothelial glycocalyx biomarkers increase in patients with infection during Emergency Department treatment [J ] . J Crit Care , 2017 , 42 : 304 - 309 .
Wang Y , Shi YX , Shao YW , et al . S100A8/A9hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis [J ] . Cell Death Dis , 2024 , 15 : 462 .
Long DD , Lu ZY , Fang B , et al . Single-cell multi-omics reveals SLC2A1-driven glycolytic reprogramming of pulmonary endothelial cells in sepsis-associated lung injury [J ] . Biochim Biophys Acta Mol Basis Dis , 2026 , 1872 ( 1 ): 168050 .
Gould S , Herron A , Davis J , et al . Control of inflammatory lung injury and repair by metabolic signaling in endothelial cells [J ] . Curr Opin Hematol , 2025 , 32 ( 3 ): 157 - 167 .
Sun HJ , Zheng GL , Wang ZC , et al . Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming [J ] . Phytomedicine , 2024 , 123 : 155175 .
Zhu JJ , Jin ZX , Wang J , et al . FGF21 ameliorates septic liver injury by restraining proinflammatory macrophages activation through the autophagy/HIF-1α axis [J ] . J Adv Res , 2025 , 69 : 477 - 494 .
Molema G , Zijlstra JG , van Meurs M , et al . Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury [J ] . Nat Rev Nephrol , 2022 , 18 ( 2 ): 95 - 112 .
Tan CY , Gu J , Li T , et al . Inhibition of aerobic glycolysis alleviates sepsis-induced acute kidney injury by promoting lactate/Sirtuin 3/AMPK-regulated autophagy [J ] . Int J Mol Med , 2021 , 47 ( 3 ): 19 .
Yang WY , Tang R , Zhou Y , et al . Succinic acid-induced macrophage endocytosis promotes extracellular vesicle-based integrin Beta1 transfer accelerating fibroblast activation and sepsis-associated pulmonary fibrosis [J ] . Adv Sci , 2025 , 12 ( 43 ): e07411 .
Zhang TN , Huang XM , Li L , et al . Lactylation of HADHA promotes sepsis-induced myocardial depression [J ] . Circ Res , 2025 , 137 ( 4 ): e65 - e87 .
陈梦瑞 , 谭小华 , 钟文静 , 等 . 衣康酸通过抑制神经损伤诱导蛋白1介导的质膜破裂减轻脓毒症急性肺损伤巨噬细胞泛凋亡 [J ] . 中南大学学报(医学版) , 2025 , 50 ( 6 ): 970 - 985 .
Chen MR , Tan XH , Zhong WJ , et al . Itaconic acid alleviates macrophage PANoptosis in sepsis-associated acute lung injury via inhibiting ninjurin-1-media ted plasma membrane rupture [J ] . J Cent South Univ Med Sci , 2025 , 50 ( 6 ): 970 - 985 .
Zhou P , Yang L , Li RD , et al . IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway [J ] . Int Immunopharmacol , 2024 , 135 : 112277 .
Wang J , Sun YZ , Teng SN , et al . Prediction of sepsis mortality using metabolite biomarkers in the blood:a meta-analysis of death-related pathways and prospective validation [J ] . BMC Med , 2020 , 18 ( 1 ): 83 .
He RY , Liu BH , Xiong R , et al . Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury [J ] . Cell Death Discov , 2022 , 8 : 43 .
Wang YY , Zhou M , Jiang RY , et al . Pharmacological inhibition of STING-mediated GPX4 autophagic degradation by 4-octyl itaconate ameliorates sepsis-induced acute kidney injury [J ] . Apoptosis , 2025 , 30 ( 5/6 ): 1410 - 1423 .
Li R , Ma Y , Wu HR , et al . 4-Octyl itaconate alleviates endothelial cell inflammation and barrier dysfunction in LPS-induced sepsis via modulating TLR4/MAPK/NF-κB signaling [J ] . Mol Med , 2025 , 31 ( 1 ): 240 .
Tian XF , Yuan LY , Zeng YZ . Butyrate attenuates SA-AKI by inhibiting pyroptosis via the STING-GSDMD axis [J ] . Biochem Biophys Res Commun , 2025 , 743 : 151143 .
Li ZY , Zhang FX , Sun MS , et al . The modulatory effects of gut microbes and metabolites on blood-brain barrier integrity and brain function in sepsis-associated encephalopathy [J ] . PeerJ , 2023 , 11 : e15122 .
Zhao LW , Huang Y , Ye ZW , et al . Short-chain fatty acids attenuate sepsis-induced gut dysbiosis and hippocampal neuroinflammation via NLRP6 inflammasome activation in mice [J ] . Int J Surg , 2026 , 112 ( 1 ): 570 - 582 .
Ji R , Chen W , Wang Y , et al . The warburg effect promotes mitochondrial injury regulated by uncoupling protein-2 in septic acute kidney injury [J ] . Shock , 2021 , 55 ( 5 ): 640 - 648 .
Li FY , Liu XQ , Yu Z , et al . 2-Deoxy-D-glucose reshapes the sepsis-trained stressed granulocytes by comprehensive alterations of the transcriptional landscape [J ] . Gene , 2025 , 972 : 149828 .
Zheng ZB , Ma H , Zhang X , et al . Enhanced glycolytic metabolism contributes to cardiac dysfunction in polymicrobial sepsis [J ] . J Infect Dis , 2017 , 215 ( 9 ): 1396 - 1406 .
Luo P , Zhang Q , Zhong TY , et al . Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect [J ] . Mil Med Res , 2022 , 9 ( 1 ): 22 .
He YY , Xie WL , Zhou HF , et al . Dexmedetomidine alleviates sepsis-induced acute lung injury by inhibiting M1 macrophage polarization via inhibition of PKM2-mediated Warburg effect [J ] . Biochem Pharmacol , 2025 , 241 : 117130 .
Gong FC , Li RR , Zheng XT , et al . OLFM4 regulates lung epithelial cell function in sepsis-associated ARDS/ALI via LDHA-mediated NF-κB signaling [J ] . J Inflamm Res , 2021 , 14 : 7035 - 7051 .
Liang HY , Song H , Zhang XJ , et al . Metformin attenuated sepsis-related liver injury by modulating gut microbiota [J ] . Emerg Microbes Infect , 2022 , 11 ( 1 ): 815 - 828 .
Fan SY , Zhao ZC , Liu XL , et al . Metformin mitigates sepsis-induced acute lung injury and inflammation in young mice by suppressing the S100A8/A9-NLRP3-IL-1β signaling pathway [J ] . J Inflamm Res , 2024 , 17 : 3785 - 3799 .
Qin ZH , Zhou CL , Xiao XC , et al . Metformin attenuates sepsis-induced neuronal injury and cognitive impairment [J ] . BMC Neurosci , 2021 , 22 ( 1 ): 78 .
0
Views
0
下载量
0
CSCD
Publicity Resources
Related Articles
Related Author
Related Institution
京公网安备11010802024621
