Unveiling the Role of LncRNA in Sepsis-Associated Encephalopathy

Xin-yue Shi , Hui Zhong , You Shang , Ding-yu Zhang , Shang-wen Pan

Current Medical Science ›› 2025, Vol. 45 ›› Issue (6) : 1336 -1347.

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Current Medical Science ›› 2025, Vol. 45 ›› Issue (6) :1336 -1347. DOI: 10.1007/s11596-025-00122-3
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Unveiling the Role of LncRNA in Sepsis-Associated Encephalopathy

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Abstract

Sepsis-associated encephalopathy (SAE) is a critical consequence of sepsis, marked by elevated morbidity and fatality rates. An unbalanced inflammatory response is a significant pathogenic mechanism. The blood-brain barrier (BBB) is an essential element of the central nervous system (CNS). Sepsis can impact the BBB and neural networks in multiple ways, especially via microglia, astrocytes, and neurons. Long non-coding RNAs (lncRNAs) can participate in the development of various diseases by modulating inflammatory responses, cellular metabolism, and immune cell functions. They not only impact the BBB but also directly influence neurons, affecting the development and prognosis of SAE. This review summarizes the current research status of lncRNAs in SAE, highlights the latest research advances of lncRNAs in sepsis and related diseases, and aims to explore their new application prospects in SAE, offering new targets and methodologies for its diagnosis and therapy.

Keywords

Sepsis-associated encephalopathy / LncRNA / Blood-brain barrier / Diagnosis / Treatment

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Xin-yue Shi, Hui Zhong, You Shang, Ding-yu Zhang, Shang-wen Pan. Unveiling the Role of LncRNA in Sepsis-Associated Encephalopathy. Current Medical Science, 2025, 45(6): 1336-1347 DOI:10.1007/s11596-025-00122-3

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References

[1]

Lu X, Qin M, Walline JH, et al.. Clinical phenotypes of sepsis-associated encephalopathy: A retrospective cohort study. Shock., 2023, 59(4): 583-590

[2]

Iwashyna TJ, Ely EW, Smith DM, et al.. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA., 2010, 304(16): 1787-1794

[3]

Mazeraud A, Righy C, Bouchereau E, et al.. Septic-associated encephalopathy: A comprehensive review. Neurotherapeutics., 2020, 17(2): 392-403

[4]

Barbosa-Silva MC, Lima MN, Battaglini D, et al.. Infectious disease-associated encephalopathies. Crit Care., 2021, 25(1): 236

[5]

Ren C, Yao RQ, Zhang H, et al.. Sepsis-associated encephalopathy: A vicious cycle of immunosuppression. J Neuroinflammation., 2020, 17(114

[6]

Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet., 2016, 17(147-62

[7]

Statello L, Guo C, Chen L, et al.. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol., 2021, 22(2): 96-118

[8]

Nemeth K, Bayraktar R, Ferracin M, et al.. Non-coding RNAs in disease: From mechanisms to therapeutics. Nat Rev Genet., 2024, 25(3): 211-232

[9]

Zhou S, Yu X, Wang M, et al.. Long non-coding RNAs in pathogenesis of neurodegenerative diseases. Front Cell Dev Biol., 2021, 9 719247

[10]

Nandwani A, Rathore S, Datta M. LncRNAs in cancer: Regulatory and therapeutic implications. Cancer Lett., 2021, 501: 162-171

[11]

Tian M, Zhan Y, Cao J, et al.. Targeting blood-brain barrier for sepsis-associated encephalopathy: Regulation of immune cells and ncRNAs. Brain Res Bull., 2024, 209 110922

[12]

Yang X, Zhang Y, Chen Y, et al.. LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1alpha expression. J Neuroinflammation., 2021, 18(1): 197

[13]

Daneman R, Prat A. The blood-brain barrier. Cold Spring Harbor Perspect Biol., 2015, 7(1 a020412

[14]

Peng X, Luo Z, He S, et al.. Blood-brain barrier disruption by lipopolysaccharide and sepsis-associated encephalopathy. Front Cell Infect Microbiol., 2021, 11 768108

[15]

Kikuchi DS, Campos ACP, Qu H, et al.. Poldip2 mediates blood-brain barrier disruption in a model of sepsis-associated encephalopathy. J Neuroinflammation., 2019, 16(1241

[16]

Wang J, Feng Q, Wu Y, et al.. Involvement of blood lncRNA UCA1 in sepsis development and prognosis, and its correlation with multiple inflammatory cytokines. J Clin Lab Anal., 2022, 36(6 e24392

[17]

Hu X, Hu A, Luo Y, et al.. LncRNA HCP5 acts as a potential diagnostic biomarker and attenuates the inflammatory response in neonatal sepsis by targeting miR-138-5p/SIRT1. Cent Eur J Immunol., 2024, 49(3216-226

[18]

Bi C, Wang D, Hao B, et al.. Snhg14/miR-181a-5p axis-mediated "M1" macrophages aggravate LPS-induced myocardial cell injury. Heliyon., 2024, 10(18 e37104

[19]

Xiao T, Sun C, Xiao Y, et al.. lncRNA NEAT1 mediates sepsis progression by regulating Irak2 via sponging miR-370–3p. Biol Open, 2024, 9(6bio049353

[20]

Zheng X, Xiang Q, Dong X, et al.. Research progress on the changes of blood-brain barrier in sepsis-associated encephalopathy. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue., 2024, 36(8): 892-896

[21]

Gao Q, Hernandes MS. Sepsis-associated encephalopathy and blood-brain barrier dysfunction. Inflammation., 2021, 44(♠): 2143-2150

[22]

Kodali MC, Chen H, Liao FF. Temporal unsnarling of brain's acute neuroinflammatory transcriptional profiles reveals panendothelitis as the earliest event preceding microgliosis. Mol Psychiatry., 2021, 26(8): 3905-3919

[23]

Islam R, Lai C. A brief overview of lncRNAs in endothelial dysfunction-associated diseases: From discovery to characterization. Epigenomes., 2019, 3(3): 20

[24]

Zhao X, Zeng H, Lei L, et al.. Tight junctions and their regulation by non-coding RNAs. Int J Biol Sci., 2021, 17(3712-727

[25]

Canovas-Cervera I, Nacher-Sendra E, Osca-Verdegal R, et al.. The intricate role of non-coding RNAs in sepsis-associated disseminated intravascular coagulation. Int J Mol Sci., 2023, 24(3): 2582

[26]

Xue J, Zhang Z, Sun Y, et al.. Research progress and molecular mechanisms of endothelial cells inflammation in vascular-related diseases. J Inflamm Res., 2023, 16: 3593-3617

[27]

Michalik KM, You X, Manavski Y, et al.. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res., 2014, 114(91389-1397

[28]

Chen J, Tang S, Ke S, et al.. Ablation of long noncoding RNA MALAT1 activates antioxidant pathway and alleviates sepsis in mice. Redox Biol., 2022, 54 102377

[29]

Wei S, Liu Q. Long noncoding RNA MALAT1 modulates sepsis-induced cardiac inflammation through the miR-150-5p/NF-kappaB axis. Int J Clin Exp Pathol., 2019, 12(9): 3311-3319

[30]

Wu K, Yu X, Wang Y, et al.. MALAT1 derepresses miR-433-3P-mediated rptor suppression to impair autophagy and drive pyroptosis in endotoxemia. Shock., 2024, 61(3): 477-489

[31]

Yan R, Liang X, Hu J. MALAT1 promotes colonic epithelial cell apoptosis and pyroptosis by sponging miR-22-3p to enhance NLRP3 expression. PeerJ., 2024, 12 e18449

[32]

Chen Y, Fu Y, Song YF, et al.. Increased Expression of lncRNA UCA1 and HULC Is Required for Pro-inflammatory Response During LPS Induced Sepsis in Endothelial Cells. Front Physiol., 2019, 10: 608

[33]

Xue R, Yiu WH, Chan KW, et al.. Long Non-coding RNA NEAT1, NOD-like receptor family protein 3 inflammasome, and acute kidney injury. J Am Soc Nephrol., 2024, 35(8): 998-1015

[34]

Wei XB, Jiang WQ, Zeng JH, et al.. Exosome-derived lncRNA NEAT1 exacerbates sepsis-associated encephalopathy by promoting ferroptosis through regulating miR-9-5p/TFRC and GOT1 axis. Mol Neurobiol., 2022, 59(31954-1969

[35]

Zhang Z, Lv M, Wang X, et al.. LncRNA LUADT1 sponges miR-195 to prevent cardiac endothelial cell apoptosis in sepsis. Mol Med., 2020, 26(1): 112

[36]

Saitoh Y, Suzuki H, Tani K, et al.. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin. Science., 2015, 347(6223775-778

[37]

Erikson K, Tuominen H, Vakkala M, et al.. Brain tight junction protein expression in sepsis in an autopsy series. Crit Care., 2020, 24(1): 385

[38]

Guo J, Cai H, Zheng J, et al.. Long non-coding RNA NEAT1 regulates permeability of the blood-tumor barrier via miR-181d-5p-mediated expression changes in ZO-1, occludin, and claudin-5. Biochim Biophys Acta Mol Basis Dis., 2017, 1863(92240-2254

[39]

Wang Y, Mao J, Li X, et al.. lncRNA HOTAIR mediates OGD/R-induced cell injury and angiogenesis in a EZH2-dependent manner. Exp Ther Med., 2022, 23(1): 99

[40]

Yu H, Xue Y, Wang P, et al.. Knockdown of long non-coding RNA XIST increases blood-tumor barrier permeability and inhibits glioma angiogenesis by targeting miR-137. Oncogenesis., 2017, 6(3 e303

[41]

Yang F, Zhang Y, Zhu J, et al.. Laminar flow protects vascular endothelial tight junctions and barrier function via maintaining the expression of long non-coding RNA MALAT1. Front Bioeng Biotechnol., 2020, 8: 647

[42]

Iba T, Helms J, Connors JM, et al.. The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation. J Intensive Care., 2023, 11(124

[43]

Joffre J, Hellman J, Ince C, et al.. Endothelial responses in sepsis. Am J Respir Crit Care Med., 2020, 202(3361-370

[44]

Molema G, Zijlstra JG, van Meurs M, et al.. Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury. Nat Rev Nephrol., 2022, 18(295-112

[45]

Zeng R, Song XJ, Liu CW, et al.. LncRNA ANRIL promotes angiogenesis and thrombosis by modulating microRNA-99a and microRNA-449a in the autophagy pathway. Am J Transl Res., 2019, 11(12): 7441-7448

[46]

Gui F, Peng H, Liu Y. Elevated circulating lnc-ANRIL/miR-125a axis level predicts higher risk, more severe disease condition, and worse prognosis of sepsis. J Clin Lab Anal., 2019, 33(6 e22917

[47]

Cao G, Zhou H, Wang D, et al.. Knockdown of lncRNA XIST ameliorates IL-1beta-Induced apoptosis of HUVECs and change of tissue factor level via miR-103a-3p/HMGB1 axis in deep venous thrombosis by regulating the ROS/NF-kappaB signaling pathway. Cardiovasc Ther., 2022, 2022(1): 6256384

[48]

Stark K, Philippi V, Stockhausen S, et al.. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood., 2016, 128(202435-2449

[49]

Endo F, Kasai A, Soto JS. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease. Science, 2022, 378(6619 eadc9020

[50]

Diaz-Castro B, Robel S, Mishra A. Astrocyte endfeet in brain function and pathology: Open questions. Annu Rev Neurosci., 2023, 46(1): 101-121

[51]

Mei B, Xu X, Weng J, et al.. Activating astrocytic alpha2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice. Brain Behav Immun., 2024, 117: 376-398

[52]

Zhu DD, Huang YL, Guo SY, et al.. AQP4 aggravates cognitive impairment in sepsis-associated encephalopathy through inhibiting Na(v) 1.6-Mediated astrocyte autophagy. Adv Sci (Weinh)., 2023, 10(1 e2205862

[53]

Shan W, Chen W, Zhao X, et al.. Long noncoding RNA TUG1 contributes to cerebral ischaemia/reperfusion injury by sponging mir-145 to up-regulate AQP4 expression. J Cell Mol Med., 2020, 24(1): 250-259

[54]

Wang H, Zheng X, Jin J, et al.. LncRNA MALAT1 silencing protects against cerebral ischemia-reperfusion injury through miR-145 to regulate AQP4. J Biomed Sci., 2020, 27(1): 40

[55]

Nakano M, Kubota K, Kobayashi E, et al.. Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer's disease model by increasing the expression of microRNA-146a in hippocampus. Sci Rep., 2020, 10(110772

[56]

Li X, Li Y, Jin Y, et al.. Transcriptional and epigenetic decoding of the microglial aging process. Nat Aging., 2023, 3(101288-1311

[57]

Hong Y, Chen P, Gao J, et al.. Sepsis-associated encephalopathy: From pathophysiology to clinical management. Int Immunopharmacol., 2023, 124(Pt A 110800

[58]

Yan X, Yang K, Xiao Q, et al.. Central role of microglia in sepsis-associated encephalopathy: From mechanism to therapy. Front Immunol., 2022, 13 929316

[59]

Hu J, Xie S, Zhang H, et al.. Microglial activation: Key players in sepsis-associated encephalopathy. Brain Sci., 2023, 13(10): 1453

[60]

Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol., 2008, 8(12958-969

[61]

Feng X, Zhan F, Luo D, et al.. LncRNA 4344 promotes NLRP3-related neuroinflammation and cognitive impairment by targeting miR-138-5p. Brain Behav Immun., 2021, 98: 283-298

[62]

Ma W, Zhang W, Cui B, et al.. Functional delivery of lncRNA TUG1 by endothelial progenitor cells derived extracellular vesicles confers anti-inflammatory macrophage polarization in sepsis via impairing miR-9-5p-targeted SIRT1 inhibition. Cell Death Dis., 2021, 12(11): 1056

[63]

Jin F, Ou W, Wei B, et al.. Transcriptome-Wide analysis to identify the inflammatory role of lncRNA Neat1 in experimental ischemic stroke. J Inflamm Res., 2021, 14: 2667-2680

[64]

Li Z, Meng X, Wu P, et al.. Glioblastoma cell-derived lncRNA-containing exosomes induce microglia to produce complement C5, promoting chemotherapy resistance. Cancer Immunol Res., 2021, 9(121383-1399

[65]

He X, Huang Y, Liu Y, et al.. Astrocyte-derived exosomal lncRNA 4933431K23Rik modulates microglial phenotype and improves post-traumatic recovery via SMAD7 regulation. Mol Ther., 2023, 31(5): 1313-1331

[66]

Zheng X, Wang M, Liu S, et al.. A lncRNA-encoded mitochondrial micropeptide exacerbates microglia-mediated neuroinflammation in retinal ischemia/reperfusion injury. Cell Death Dis., 2023, 14(2): 126

[67]

Messemaker TC, van Leeuwen SM, van den Berg PR, et al.. Allele-specific repression of Sox2 through the long non-coding RNA Sox2ot. Sci Rep., 2018, 8(1386

[68]

Yin J, Shen Y, Si Y, et al.. Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy. J Neuroinflammation., 2020, 17(1320

[69]

Balusu S, Horre K, Thrupp N, et al.. MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease. Science., 2023, 381(66631176-1182

[70]

Bernard D, Prasanth KV, Tripathi V, et al.. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J., 2010, 29(18): 3082-3093

[71]

Tang C, Jin Y, Wang H. The biological alterations of synapse/synapse formation in sepsis-associated encephalopathy. Front Synaptic Neurosci., 2022, 14: 1054605

[72]

Moraes CA, Santos G, de Sampaio e Spohr TC, et al.. Activated microglia-induced deficits in excitatory synapses through IL-1β: Implications for cognitive impairment in sepsis. Neurobiol, 2015, 52(1): 653-663

[73]

Wu Y, Li P, Liu L, et al.. lncRNA Neat1 regulates neuronal dysfunction post-sepsis via stabilization of hemoglobin subunit beta. Mol Ther., 2022, 30(72618-2632

[74]

Wang F, Wang Q, Liu B, et al.. The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum. Cell Death Differ., 2021, 28(9): 2634-2650

[75]

Wang C, Dong J, Sun J, et al.. Silencing of lncRNA XIST impairs angiogenesis and exacerbates cerebral vascular injury after ischemic stroke. Mol Ther Nucleic Acids., 2021, 26: 148-160

[76]

Dong X, Zhao Y, Huang Y, et al.. Analysis of long noncoding RNA expression profiles in the whole blood of neonates with hypoxic-ischemic encephalopathy. J Cell Biochem., 2019, 120(5): 8499-8509

[77]

Patel RS, Krause-Hauch M, Kenney K, et al.. Long noncoding RNA VLDLR-AS1 levels in serum correlate with combat-related chronic mild traumatic brain injury and depression symptoms in US veterans. Int J Mol Sci., 2024, 25(3): 1473

[78]

Liu B, Ren H, Chen J. LncRNA NEAT1 correlates with Th1 and Th17 and could serve as an assistant biomarker in sepsis. Biomark Med., 2021, 15(131177-1186

[79]

Dai Y, Liang Z, Li Y, et al.. Circulating long noncoding RNAs as potential biomarkers of sepsis: A preliminary study. Genet Test Mol Biomarkers., 2017, 21(11): 649-657

[80]

Luo X, Chen X, Gu Y, et al.. LncRNA FENDRR/ miR-424-5p serves as a diagnostic biomarker for sepsis and its predictive value for clinical outcomes. Immunobiology., 2025, 230(2 152870

[81]

Wei Y, Bai C, Xu S, et al.. Diagnostic and predictive value of LncRNA MCM3AP-AS1 in sepsis and its regulatory role in sepsis-induced myocardial dysfunction. Cardiovasc Toxicol., 2024, 24(10): 1125-1138

[82]

Shi W, Zhu W, Yu J, et al.. LncRNA HOTTIP as a diagnostic biomarker for acute respiratory distress syndrome in patients with sepsis and to predict the short-term clinical outcome: A case-control study. BMC Anesthesiol., 2024, 24(1): 30

[83]

Osca-Verdegal R, Beltran-Garcia J, Pallardo FV, et al.. Role of microRNAs as biomarkers in sepsis-associated encephalopathy. Mol Neurobiol., 2021, 58(94682-4693

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