Role of oxidative stress in sepsis: Mechanisms, pathways, and therapeutic strategies

Xin-Ru Yang; Ri Wen; Ni Yang; Yang Gao; Tie-Ning Zhang

doi:10.1016/j.jpha.2025.101452

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2025 > Accepted Manu

Xin-Ru Yang, Ri Wen, Ni Yang, Yang Gao, Tie-Ning Zhang. Role of oxidative stress in sepsis: Mechanisms, pathways, and therapeutic strategies[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101452

Citation:

Xin-Ru Yang, Ri Wen, Ni Yang, Yang Gao, Tie-Ning Zhang. Role of oxidative stress in sepsis: Mechanisms, pathways, and therapeutic strategies[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101452

Citation:

PDF( 5174 KB)

Role of oxidative stress in sepsis: Mechanisms, pathways, and therapeutic strategies

doi: 10.1016/j.jpha.2025.101452

Department of Pediatrics, Pediatric Intensive Care Unit, Shengjing Hospital of China Medical University, Shenyang, 110004, China

Funds:

The authors thank all research team members for their contributions to this work. The figures are created with BioRender.com.

Received Date: Mar. 11, 2025
Accepted Date: Sep. 12, 2025
Rev Recd Date: Sep. 08, 2025
Available Online: Sep. 25, 2025

Abstract

Abstract

Sepsis, a life-threatening condition caused by dysregulated host response to infection, leads to high morbidity and mortality, primarily due to sepsis-induced organ dysfunction. Oxidative stress, driven by excessive reactive oxygen species (ROS), plays a central role in sepsis pathophysiology, exacerbating inflammation, mitochondrial dysfunction, and cellular damage in multiple organs, including the heart, kidneys, liver, lungs, brain, and skeletal muscles. This review provides a comprehensive analysis of mechanisms by which oxidative stress contributes to sepsis-induced organ injury. Most current research examining the interplay between ROS, inflammation, mitochondrial dysfunction, and cell death pathways such as apoptosis, ferroptosis, and pyroptosis, are animal- or cell-based. Key signaling pathways, including nuclear factor κB (NF-κB), NLR family pyrin domain-containing 3 inflammasome (NLRP3), nuclear factor erythroid 2-related factor 2 /heme oxygenase-1 (Nrf-2/HO-1), and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), are explored as potential therapeutic targets. This review also highlights the roles of mitochondrial quality control, autophagy, and noncoding RNAs in mitigating oxidative damage.
- Oxidative stress,
- Sepsis,
- Organ dysfunction,
- Mitochondrial dysfunction

FullText(HTML)

References(150)

References

[1]	M. Singer, C.S. Deutschman, C.W. Seymour, et al., The third international consensus definitions for sepsis and septic shock (sepsis-3), Jama 315 (2016), 801.
[2]	L. Evans, A. Rhodes, W. Alhazzani, et al., Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021, Intensive Care Med. 47 (2021) 1181-1247.
[3]	K.E. Rudd, S.C. Johnson, K.M. Agesa, et al., Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study, Lancet 395 (2020) 200-211.
[4]	K.M. Holmstrom, T. Finkel, Cellular mechanisms and physiological consequences of redox-dependent signalling, Nat. Rev. Mol. Cell Biol. 15 (2014) 411-421.
[5]	J.E. Gotts, M.A. Matthay, Sepsis: Pathophysiology and clinical management, Bmj (2016), i1585.
[6]	Y Wang, Z Liu, M Zhang, et al., Mucosa-associated lymphoid tissue lymphoma translocation protein 1 exaggerates multiple organ injury, inflammation, and immune cell imbalance by activating the NF-κB pathway in sepsis, Front. Microbiol. 14 (2023), 1117285.
[7]	X. Chen, J. Cui, X. Meng, et al., Angiotensin-(1-7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-κB and MAPK pathways, J. Transl. Med. 21 (2023), 2.
[8]	C. Piamsiri, C. Maneechote, S.C. Chattipakorn, et al., Therapeutic potential of gasdermin D-mediated myocardial pyroptosis in ischaemic heart disease: Expanding the paradigm from bench to clinical insights, J. Cell. Mol. Med. 29 (2025), e70357.
[9]	G He, K Chen, H Wang, et al., Fudosteine attenuates acute lung injury in septic mice by inhibiting pyroptosis via the TXNIP/NLRP3/GSDMD pathway, Eur. J. Pharmacol. 926 (2022), 175047.
[10]	T. Weiss-Sadan, M Ge, M. Hayashi, et al., NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer, Cell Metab. 35 (2023) 487-503.e7.
[11]	B.S. Sailaja, R. Aita, S. Maledatu, et al., Moringa isothiocyanate -1-1 regulates Nrf2 and NF-κB pathway in response to LPS-driven sepsis and inflammation, PLoS One 16 (2021), e0248691.
[12]	G. Wang, F. Ma, W. Zhang, et al., Malvidin alleviates LPS-induced septic intestinal injury through the nuclear factor erythroid 2-related factor 2/reactive oxygen species/NLRP3 inflammasome pathway, Inflammopharmacology 32 (2024) 893-901.
[13]	Q Wu, Y Wang, Q Li, Matairesinol exerts anti-inflammatory and antioxidant effects in sepsis-mediated brain injury by repressing the MAPK and NF-κB pathways through up-regulating AMPK, Aging (2021) 23780-23795.
[14]	J Xu, L Tao, L Jiang, et al., Moderate hypothermia alleviates sepsis-associated acute lung injury by suppressing ferroptosis induced by excessive inflammation and oxidative stress via the Keap1/GSK3β/Nrf2/GPX4 signaling pathway, J. Inflamm. Res. 17 (2024) 7687-7704.
[15]	D Liang, A.M. Minikes, X Jiang, Ferroptosis at the intersection of lipid metabolism and cellular signaling, Mol. Cell 82 (2022) 2215-2227.
[16]	Y Li, L Huang, J Li, et al., Targeting TLR4 and regulating the Keap1/Nrf2 pathway with andrographolide to suppress inflammation and ferroptosis in LPS-induced acute lung injury, Chin. J. Nat. Med. 22 (2024) 914-928.
[17]	J Li, C Ren, L Wang, et al., Sestrin2 protects dendrite cells against ferroptosis induced by sepsis, Cell Death Dis. 12 (2021), 834.
[18]	J Song, J.M. Herrmann, T. Becker, Quality control of the mitochondrial proteome, Nat. Rev. Mol. Cell Biol. 22 (2021) 54-70.
[19]	X Zhang, J.E. Griepentrog, B Zou, et al., CaMKIV regulates mitochondrial dynamics during sepsis, Cell Calcium 92 (2020), 102286.
[20]	W. Di, Z. Jin, W. Lei, et al., Protection of melatonin treatment and combination with traditional antibiotics against septic myocardial injury, Cell. Mol. Biol. Lett. 28 (2023), 35.
[21]	Z Deng, M He, H Hu, et al., Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation, Autophagy 20 (2024) 151-165.
[22]	N. Li, R. Xiong, G. Li, et al., A novel mechanism for the protection against acute lung injury by melatonin: Mitochondrial quality control of lung epithelial cells is preserved through SIRT3-dependent deacetylation of SOD2, Cell. Mol. Life Sci. 79 (2022), 610.
[23]	D. Senft, Z.A. Ronai, UPR, autophagy, and mitochondria crosstalk underlies the ER stress response, Trends Biochem. Sci. 40 (2015) 141-148.
[24]	D Li, C Li, T Wang, et al., Geranylgeranyl diphosphate synthase 1 knockdown suppresses NLRP3 inflammasome activity via promoting autophagy in sepsis-induced acute lung injury, Int. Immunopharmacol. 100 (2021), 108106.
[25]	P.N. Shiroorkar, O. Afzal, I. Kazmi, et al., Cardioprotective effect of tangeretin by inhibiting PTEN/AKT/mTOR axis in experimental sepsis-induced myocardial dysfunction, Molecules 25 (2020), 5622.
[26]	M. Mohsin, G. Tabassum, S. Ahmad, et al., The role of mitophagy in pulmonary sepsis, Mitochondrion 59 (2021) 63-75.
[27]	M. L’Heureux, M. Sternberg, L. Brath, et al., Sepsis-induced cardiomyopathy: A comprehensive review, Curr. Cardiol. Rep. 22 (2020), 35.
[28]	F Li, F Lang, Y Wang, et al., Cyanidin ameliorates endotoxin-induced myocardial toxicity by modulating inflammation and oxidative stress through mitochondria and other factors, Food Chem. Toxicol. 120 (2018) 104-111.
[29]	P.R. Nunes, S.V. Mattioli, V.C. Sandrim, NLRP3 activation and its relationship to endothelial dysfunction and oxidative stress: Implications for preeclampsia and pharmacological interventions, Cells 10 (2021), 2828.
[30]	W Lei, X Xu, N Li, et al., Isopropyl 3-(3, 4-dihydroxyphenyl) 2-hydroxypropanoate protects septic myocardial injury via regulating GAS6/Axl-AMPK signaling pathway, Biochem. Pharmacol. 221 (2024), 116035.
[31]	C. Deng, Q. Liu, H. Zhao, et al., Activation of NR1H3 attenuates the severity of septic myocardial injury by inhibiting NLRP3 inflammasome, Bioeng. Transl. Med. 8 (2023) e10517.
[32]	Z Li, J Zhou, S Cui, et al., Activation of sigma-1 receptor ameliorates sepsis-induced myocardial injury by mediating the Nrf2/HO1 signaling pathway to attenuate mitochondrial oxidative stress, Int. Immunopharmacol. 127 (2024), 111382.
[33]	Z Wang, N Yang, Y Hou, et al., L-arginine-loaded gold nanocages ameliorate myocardial ischemia/reperfusion injury by promoting nitric oxide production and maintaining mitochondrial function, Adv. Sci. 10 (2023), e2302123.
[34]	M.S. Joshi, M.W. Julian, J.E. Huff, et al., Calcineurin regulates myocardial function during acute endotoxemia, Am. J. Respir. Crit. Care Med. 173 (2006) 999-1007.
[35]	N Zhang, Y Zhang, H Qian, et al., Selective targeting of ubiquitination and degradation of PARP1 by E3 ubiquitin ligase WWP2 regulates isoproterenol-induced cardiac remodeling, Cell Death Differ. 27 (2020) 2605-2619.
[36]	D Wang, Z Lin, Y Zhou, et al., Atractylenolide I ameliorates sepsis-induced cardiomyocyte injury by inhibiting macrophage polarization through the modulation of the PARP1/NLRP3 signaling pathway, Tissue Cell 89 (2024), 102424.
[37]	C Liu, Q Zou, H Tang, et al., Melanin nanoparticles alleviate sepsis-induced myocardial injury by suppressing ferroptosis and inflammation, Bioact. Mater. 24 (2023) 313-321.
[38]	H. Liu, Q. Hu, K. Ren, et al., ALDH2 mitigates LPS-induced cardiac dysfunction, inflammation, and apoptosis through the cGAS/STING pathway, Mol. Med. 29 (2023), 171.
[39]	S Qin, Y Ren, B Feng, et al., ANXA1sp protects against sepsis-induced myocardial injury by inhibiting ferroptosis-induced cardiomyocyte death via SIRT3-mediated p53 deacetylation, Mediat. Inflamm. 2023 (2023), 6638929.
[40]	J Hu, Y Xue, K Tang, et al., The protective effects of hydrogen sulfide on the myocardial ischemia via regulating Bmal1, Biomed. Pharmacother. 120 (2019), 109540.
[41]	H. Lin, F. Ji, K. Lin, et al., LPS-aggravated ferroptosis via disrupting circadian rhythm by Bmal1/AKT/p53 in sepsis-induced myocardial injury, Inflammation 46 (2023) 1133-1143.
[42]	H. Zhu, J. Wang, T. Xin, et al., DUSP1 interacts with and dephosphorylates VCP to improve mitochondrial quality control against endotoxemia-induced myocardial dysfunction, Cell. Mol. Life Sci. 80 (2023), 213.
[43]	C Cai, Z Li, Z Zheng, et al., Pgam5-mediated PHB2 dephosphorylation contributes to endotoxemia-induced myocardial dysfunction by inhibiting mitophagy and the mitochondrial unfolded protein response, Int. J. Biol. Sci. 19 (2023) 4657-4671.
[44]	D Hou, H Liao, S Hao, et al., Curcumin simultaneously improves mitochondrial dynamics and myocardial cell bioenergy after sepsis via the SIRT1-DRP1/PGC-1α pathway, Heliyon 10 (2024), e28501.
[45]	C. Koentges, M.C. Cimolai, K. Pfeil, et al., Impaired SIRT3 activity mediates cardiac dysfunction in endotoxemia by calpain-dependent disruption of ATP synthesis, J. Mol. Cell. Cardiol. 133 (2019) 138-147.
[46]	J.P. Sanchez-Villamil, V. D’Annunzio, P. Finocchietto, et al., Cardiac-specific overexpression of thioredoxin 1 attenuates mitochondrial and myocardial dysfunction in septic mice, Int. J. Biochem. Cell Biol. 81 (2016) 323-334.
[47]	S Liu, F Liu, J Yan, et al., The Elabela-APJ axis attenuates sepsis-induced myocardial dysfunction by reducing pyroptosis by balancing the formation and degradation of autophagosomes, Free. Radic. Biol. Med. 224 (2024) 405-417.
[48]	Y Wang, H. Jasper, S. Toan, et al., Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury, Redox Biol. 45 (2021), 102049.
[49]	W Ji, T Wan, F Zhang, et al., Aldehyde dehydrogenase 2 protects against lipopolysaccharide-induced myocardial injury by suppressing mitophagy, Front. Pharmacol. 12 (2021), 641058.
[50]	N. Arulkumaran, S. Pollen, E. Greco, et al., Renal tubular cell mitochondrial dysfunction occurs despite preserved renal oxygen delivery in experimental septic acute kidney injury, Crit. Care Med. 46 (2018) e318-e325.
[51]	Y Yang, J Xu, J Tu, et al., Polygonum cuspidatum Sieb. et Zucc. Extracts improve sepsis-associated acute kidney injury by inhibiting NF-κB-mediated inflammation and pyroptosis, J. Ethnopharmacol. 319 (2024), 117101.
[52]	P Wang, J Huang, Y Li, et al., Exogenous carbon monoxide decreases sepsis-induced acute kidney injury and inhibits NLRP3 inflammasome activation in rats, Int. J. Mol. Sci. 16 (2015) 20595-20608.
[53]	X Zhu, G Zheng, Q Lu, et al., Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization, Eur. J. Pharmacol. 976 (2024), 176696.
[54]	J Sun, X Ge, Y Wang, et al., USF2 knockdown downregulates THBS1 to inhibit the TGF-β signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury, Pharmacol. Res. 176 (2022), 105962.
[55]	Y Ding, Y Zheng, J Huang, et al., UCP2 ameliorates mitochondrial dysfunction, inflammation, and oxidative stress in lipopolysaccharide-induced acute kidney injury, Int. Immunopharmacol. 71 (2019) 336-349.
[56]	N. Arulkumaran, S.J. Pollen, R. Tidswell, et al., Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats, Br. J. Anaesth. 127 (2021) 577-586.
[57]	A.J. Dare, E.A. Bolton, G.J. Pettigrew, et al., Protection against renal ischemia-reperfusion injury in vivo by the mitochondria targeted antioxidant MitoQ, Redox Biol. 5 (2015) 163-168.
[58]	H Fan, Y Sun, X Zhang, et al., Malvidin promotes PGC-1α/Nrf2 signaling to attenuate the inflammatory response and restore mitochondrial activity in septic acute kidney injury, Chem. Biol. Interact. 388 (2024), 110850.
[59]	K.A. Hershberger, A.S. Martin, M.D. Hirschey, Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases, Nat. Rev. Nephrol. 13 (2017) 213-225.
[60]	W Zhao, L Zhang, M Sui, et al., Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury, Sci. Rep. 6 (2016), 33201.
[61]	S. Zhang, X. Feng, G. Yang, et al., Dexmedetomidine ameliorates acute kidney injury by regulating mitochondrial dynamics via the α2-AR/SIRT1/PGC-1α pathway activation in rats, Mol. Med. 30 (2024), 184.
[62]	S He, Q Gao, X Wu, et al., NAD+ ameliorates endotoxin-induced acute kidney injury in a sirtuin1-dependent manner via GSK-3β/Nrf2 signalling pathway, J. Cell. Mol. Med. 26 (2022) 1979-1993.
[63]	Y Zhao, X Feng, B Li, et al., Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway, Front. Pharmacol. 11 (2020), 128.
[64]	W Zhao, L Zhang, R Chen, et al., SIRT3 protects against acute kidney injury via AMPK/mTOR-regulated autophagy, Front. Physiol. 9 (2018), 1526.
[65]	J Liu, C Yang, W Zhang, et al., Disturbance of mitochondrial dynamics and mitophagy in sepsis-induced acute kidney injury, Life Sci. 235 (2019), 116828.
[66]	Y Wang, W Lv, X Ma, et al., NDUFS3 alleviates oxidative stress and ferroptosis in sepsis induced acute kidney injury through AMPK pathway, Int. Immunopharmacol. 143 (2024), 113393.
[67]	L Zhang, J Rao, X Liu, et al., Attenuation of sepsis-induced acute kidney injury by exogenous H2S via inhibition of ferroptosis, Molecules 28 (2023), 4770.
[68]	Y Liu, L Zhou, C Lv, et al., PGE2 pathway mediates oxidative stress-induced ferroptosis in renal tubular epithelial cells, FEBS J. 290 (2023) 533-549.
[69]	H.P. Osuru, K. Ikeda, N. Atluri, et al., Moderate exercise-induced dynamics on key sepsis-associated signaling pathways in the liver, Crit. Care 27 (2023), 266.
[70]	X Zhang, C Su, S Zhao, et al., Combination therapy of Ulinastatin with Thrombomodulin alleviates endotoxin (LPS) - induced liver and kidney injury via inhibiting apoptosis, oxidative stress and HMGB1/TLR4/NF-κB pathway, Bioengineered 13 (2022) 2951-2970.
[71]	T Yang, S Zhao, N Sun, et al., Network pharmacology and in vivo studies reveal the pharmacological effects and molecular mechanisms of Celastrol against acute hepatic injury induced by LPS, Int. Immunopharmacol. 117 (2023), 109898.
[72]	L Li, Q Zhang, X Zhang, et al., Protective effects of Nrf2 against sepsis-induced hepatic injury, Life Sci. 282 (2021), 119807.
[73]	K Xie, F Wang, Y Yang, et al., Monotropein alleviates septic acute liver injury by restricting oxidative stress, inflammation, and apoptosis via the AKT (Ser473)/GSK3β (Ser9)/Fyn/NRF2 pathway, Int. Immunopharmacol. 142 (2024), 113178.
[74]	N Sun, C Shen, L Zhang, et al., Hepatic Kruppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance, Gut 70 (2021) 2183-2195.
[75]	M Zhou, Y Cao, S Xie, et al., Gypenoside XLIX alleviates acute liver injury: Emphasis on NF-κB/PPAR-α/NLRP3 pathways, Int. Immunopharmacol. 131 (2024), 111872.
[76]	P. Eyenga, D. Roussel, J. Morel, et al., Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria, J. Physiol. Biochem. 70 (2014) 285-296.
[77]	C. Doerrier, J.A. Garcia, H. Volt, et al., Identification of mitochondrial deficits and melatonin targets in liver of septic mice by high-resolution respirometry, Life Sci. 121 (2015) 158-165.
[78]	R Ding, J Han, D Zhao, et al., Pretreatment with Rho-kinase inhibitor ameliorates lethal endotoxemia-induced liver injury by improving mitochondrial function, Int. Immunopharmacol. 40 (2016) 125-130.
[79]	L Li, H Wang, S Zhao, et al., Paeoniflorin ameliorates lipopolysaccharide-induced acute liver injury by inhibiting oxidative stress and inflammation via SIRT1/FOXO1a/SOD2 signaling in rats, Phytother. Res. 36 (2022) 2558-2571.
[80]	L Huang, H.P. Dong, I.C. Chuang, et al., Attenuation of mitochondrial unfolded protein response is associated with hepatic dysfunction in septic rats, Shock 38 (2012) 642-648.
[81]	Y Yang, Q Chen, S Fan, et al., Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation, Redox Rep. 29 (2024), 2312320.
[82]	Z Jiang, L Bo, Y Meng, et al., Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy, Cell Death Dis. 9 (2018), 847.
[83]	W Xing, L Yang, Y Peng, et al., Ginsenoside Rg3 attenuates sepsis-induced injury and mitochondrial dysfunction in liver via AMPK-mediated autophagy flux, Biosci. Rep. 37 (2017), BSR20170934.
[84]	Y. Minamiyama, S. Takemura, S. Toyokuni, et al., CYP3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats, Free. Radic. Biol. Med. 37 (2004) 703-712.
[85]	N Gao, J Chen, Y Li, et al., The CYP2E1 inhibitor Q11 ameliorates LPS-induced sepsis in mice by suppressing oxidative stress and NLRP3 activation, Biochem. Pharmacol. 214 (2023), 115638.
[86]	B Sun, M Lei, J Zhang, et al., Acute lung injury caused by sepsis: How does it happen Front. Med. 10 (2023), 1289194.
[87]	G Chen, Y Hou, X Li, et al., Sepsis-induced acute lung injury in young rats is relieved by calycosin through inactivating the HMGB1/MyD88/NF-κB pathway and NLRP3 inflammasome, Int. Immunopharmacol. 96 (2021), 107623.
[88]	Z Liu, J Gao, Y Ban, et al., Synergistic effect of paeoniflorin combined with luteolin in alleviating Lipopolysaccharides-induced acute lung injury, J. Ethnopharmacol. 327 (2024), 118022.
[89]	F. Long, L. Hu, Y. Chen, et al., RBM3 is associated with acute lung injury in septic mice and patients via the NF-κB/NLRP3 pathway, Inflamm. Res. 72 (2023) 731-744.
[90]	W Tong, C Song, D Jin, et al., QSOX1 exerts anti-inflammatory effects in sepsis-induced acute lung injury: Regulation involving EGFR phosphorylation mediated M1 polarization of macrophages, Int. J. Biochem. Cell Biol. 176 (2024), 106651.
[91]	Y Li, Q Liang, L Zhou, et al., An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization, Acta Biomater. 152 (2022) 406-424.
[92]	K Yang, B Wu, W Wei, et al., Curdione ameliorates sepsis-induced lung injury by inhibiting platelet-mediated neutrophil extracellular trap formation, Int. Immunopharmacol. 118 (2023), 110082.
[93]	Y Cui, Y Yang, W Tao, et al., Neutrophil extracellular traps induce alveolar macrophage pyroptosis by regulating NLRP3 deubiquitination, aggravating the development of septic lung injury, J. Inflamm. Res. 16 (2023) 861-877.
[94]	H Zhang, J Liu, Y Zhou, et al., Neutrophil extracellular traps mediate m6A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells, Int. J. Biol. Sci. 18 (2022) 3337-3357.
[95]	J Li, M Li, L Li, et al., Hydrogen sulfide attenuates ferroptosis and stimulates autophagy by blocking mTOR signaling in sepsis-induced acute lung injury, Mol. Immunol. 141 (2022) 318-327.
[96]	J Chen, W Ding, Z Zhang, et al., Shenfu injection targets the PI3K-AKT pathway to regulate autophagy and apoptosis in acute respiratory distress syndrome caused by sepsis, Phytomedicine 129 (2024), 155627.
[97]	G Li, T Fu, W Wang, et al., Pretreatment with kahweol attenuates sepsis-induced acute lung injury via improving mitochondrial homeostasis in a CaMKKII/AMPK-dependent pathway, Mol. Nutr. Food Res. 67 (2023), e2300083.
[98]	A Dong, Y Yu, Y Wang, et al., Protective effects of hydrogen gas against sepsis-induced acute lung injury via regulation of mitochondrial function and dynamics, Int. Immunopharmacol. 65 (2018) 366-372.
[99]	S Jin, J Sun, G Liu, et al., Nrf2/PHB2 alleviates mitochondrial damage and protects against Staphylococcus aureus-induced acute lung injury, MedComm 4 (2023), e448.
[100]	J Shi, T Yu, K Song, et al., Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway, Redox Biol. 41 (2021), 101954.
[101]	K Song, J Shi, L Zhan, et al., Dexmedetomidine modulates mitochondrial dynamics to protect against endotoxin-induced lung injury via the protein kinase C-ɑ/haem oxygenase-1 signalling pathway, Biomarkers 27 (2022) 159-168.
[102]	L Zhang, S Deng, S Zhao, et al., Intra-peritoneal administration of mitochondrial DNA provokes acute lung injury and systemic inflammation via toll-like receptor 9, Int. J. Mol. Sci. 17 (2016), 1425.
[103]	N Li, W Wang, W Jiang, et al., Cytosolic DNA-STING-NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide, Clin. Transl. Med. 10 (2020), e228.
[104]	A Sang, Y Wang, S Wang, et al., Quercetin attenuates sepsis-induced acute lung injury via suppressing oxidative stress-mediated ER stress through activation of SIRT1/AMPK pathways, Cell. Signal. 96 (2022), 110363.
[105]	W Xie, L Deng, M Lin, et al., Sirtuin1 mediates the protective effects of echinacoside against sepsis-induced acute lung injury via regulating the NOX4-Nrf2 axis, Antioxidants 12 (2023), 1925.
[106]	X Li, S Wang, M Luo, et al., Carnosol alleviates sepsis-induced pulmonary endothelial barrier dysfunction by targeting nuclear factor erythroid2-related factor 2/sirtuin-3 signaling pathway to attenuate oxidative damage, Phytother. Res. 38 (2024) 2182-2197.
[107]	Z Wu, Y Wang, S Lu, et al., SIRT3 alleviates sepsis-induced acute lung injury by inhibiting pyroptosis via regulating the deacetylation of FoxO3a, Pulm. Pharmacol. Ther. 82 (2023), 102244.
[108]	N Gao, X Liu, J Chen, et al., Menaquinone-4 alleviates sepsis-associated acute lung injury via activating SIRT3-p53/SLC7A11 pathway, J. Inflamm. Res. 17 (2024) 7675-7685.
[109]	N Li, B Liu, R Xiong, et al., HDAC3 deficiency protects against acute lung injury by maintaining epithelial barrier integrity through preserving mitochondrial quality control, Redox Biol. 63 (2023), 102746.
[110]	B Liu, N Li, Y Liu, et al., BRD3308 suppresses macrophage oxidative stress and pyroptosis via upregulating acetylation of H3K27 in sepsis-induced acute lung injury, Burns Trauma 12 (2024), tkae033.
[111]	H.Y. Chung, J. Wickel, F.M. Brunkhorst, et al., Sepsis-associated encephalopathy: From delirium to dementia J. Clin. Med. 9 (2020), 703.
[112]	X Peng, Z Luo, S He, et al., Blood-brain barrier disruption by lipopolysaccharide and sepsis-associated encephalopathy, Front. Cell. Infect. Microbiol. 11 (2021), 768108.
[113]	B.I. Hudson, M.E. Lippman, Targeting RAGE signaling in inflammatory disease, Annu. Rev. Med. 69 (2018) 349-364.
[114]	L Zhang, Y Jiang, S Deng, et al., S100B/RAGE/Ceramide signaling pathway is involved in sepsis-associated encephalopathy, Life Sci. 277 (2021), 119490.
[115]	B Song, W Zhou, Amarogentin has protective effects against sepsis-induced brain injury via modulating the AMPK/SIRT1/NF-κB pathway, Brain Res. Bull. 189 (2022) 44-56.
[116]	J.S. Dumbuya, X Chen, J Du, et al., Hydrogen-rich saline regulates NLRP3 inflammasome activation in sepsis-associated encephalopathy rat model, Int. Immunopharmacol. 123 (2023), 110758.
[117]	K. Xie, Y. Zhang, Y. Wang, et al., Hydrogen attenuates sepsis-associated encephalopathy by NRF2 mediated NLRP3 pathway inactivation, Inflamm. Res. 69 (2020) 697-710.
[118]	Y Tian, L Wang, X Fan, et al., β-patchoulene alleviates cognitive dysfunction in a mouse model of sepsis associated encephalopathy by inhibition of microglia activation through Sirt1/Nrf2 signaling pathway, PLoS One 18 (2023), e0279964.
[119]	W Cui, J Chen, F Yu, et al., GYY4137 protected the integrity of the blood-brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis, FASEB J. 35 (2021), e21710.
[120]	Y. Li, T. Wan, J. Li, et al., ACE2 rescues sepsis-associated encephalopathy by reducing inflammation, oxidative stress, and neuronal apoptosis via the Nrf2/Sestrin2 signaling pathway, Mol. Neurobiol. 61 (2024) 8640-8655.
[121]	H. Wang, L. Xu, X. Tang, et al., Lipid peroxidation-induced ferroptosis as a therapeutic target for mitigating neuronal injury and inflammation in sepsis-associated encephalopathy: Insights into the hippocampal PEBP-1/15-LOX/GPX4 pathway, Lipds. Health Dis. 23 (2024), 128.
[122]	C Wang, Y Zhang, Y Yang, et al., Effect of esketamine pretreatment on acute sepsis-associated encephalopathy, Exp. Neurol. 372 (2024), 114646.
[123]	Y. Zhou, Y. Yang, L. Yi, et al., Propofol mitigates sepsis-induced brain injury by inhibiting ferroptosis via activation of the Nrf2/HO-1axis, Neurochem. Res. 49 (2024) 2131-2147.
[124]	Z. Zhou, Y. Yang, Y. Wei, et al., Remimazolam attenuates LPS-derived cognitive dysfunction via subdiaphragmatic vagus nerve target α7nAChR-mediated Nrf2/HO-1 signal pathway, Neurochem. Res. 49 (2024) 1306-1321.
[125]	B. Haileselassie, A.U. Joshi, P.S. Minhas, et al., Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy, J. Neuroinflammation 17 (2020), 36.
[126]	Y. Liu, H. Yang, N. Luo, et al., An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1/PGC-1α signaling pathway, J. Transl. Med. 21 (2023), 486.
[127]	M. Bonora, C. Giorgi, P. Pinton, Molecular mechanisms and consequences of mitochondrial permeability transition, Nat. Rev. Mol. Cell Biol. 23 (2022) 266-285.
[128]	T. Kobayashi, H. Uchino, E. Elmer, et al., Disease outcome and brain metabolomics of cyclophilin-D knockout mice in sepsis, Int. J. Mol. Sci. 23 (2022), 961.
[129]	J. Tian, Y. Tai, M. Shi, et al., Atorvastatin relieves cognitive disorder after sepsis through reverting inflammatory cytokines, oxidative stress, and neuronal apoptosis in hippocampus, Cell. Mol. Neurobiol. 40 (2020) 521-530.
[130]	N Zhang, W Zhao, Z Hu, et al., Protective effects and mechanisms of high-dose vitamin C on sepsis-associated cognitive impairment in rats, Sci. Rep. 11 (2021), 14511.
[131]	A. Della Giustina, M.P. de Souza Goldim, L.G. Danielski, et al., Lipoic acid and fish oil combination potentiates neuroinflammation and oxidative stress regulation and prevents cognitive decline of rats after sepsis, Mol. Neurobiol. 57 (2020) 4451-4466.
[132]	K Fu, C Hui, X Wang, et al., Torpor-like hypothermia induced by A1 adenosine receptor agonist: A novel approach to protect against neuroinflammation, Int. J. Mol. Sci. 24 (2023), 11036.
[133]	K.T. Cheng, S Xiong, Z Ye, et al., Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury, J. Clin. Investig. 127 (2017) 4124-4135.
[134]	B.A. Molitoris, R. Sandoval, T.A. Sutton, Endothelial injury and dysfunction in ischemic acute renal failure, Crit. Care Med. 30 (2002) S235-S240.
[135]	F.M. Wulfert, M. van Meurs, N.F. Kurniati, et al., Age-dependent role of microvascular endothelial and polymorphonuclear cells in lipopolysaccharide-induced acute kidney injury, Anesthesiology 117 (2012) 126-136.
[136]	S. Fukuda, Y. Niimi, Y. Hirasawa, et al., Modulation of oxidative and nitrosative stress attenuates microvascular hyperpermeability in ovine model of Pseudomonas aeruginosa sepsis, Sci. Rep. 11 (2021), 23966.
[137]	Z Zhan, L Chai, H Yang, et al., Endoplasmic reticulum peroxynitrite fluctuations in hypoxia-induced endothelial injury and sepsis with a two-photon fluorescence probe, Anal. Chem. 95 (2023) 5585-5593.
[138]	S. Kumar, E. Gupta, N. Gupta, et al., Functional role of iNOS-Rac2 interaction in neutrophil extracellular traps (NETs) induced cytotoxicity in sepsis, Clin. Chim. Acta 513 (2021) 43-49.
[139]	R. Osca-Verdegal, J. Beltran-Garcia, A.B. Paes, et al., Histone citrullination mediates a protective role in endothelium and modulates inflammation, Cells 11 (2022), 4070.
[140]	D. Perez-Cremades, C. Bueno-Beti, J.L. Garcia-Gimenez, et al., Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells, J. Physiol. Biochem. 79 (2023) 251-260.
[141]	L. You, D. Zhang, H. Geng, et al., Salidroside protects endothelial cells against LPS-induced inflammatory injury by inhibiting NLRP3 and enhancing autophagy, BMC Complementary Med. Ther. 21 (2021), 146.
[142]	Y. Bai, D. Yan, H. Zhou, et al., Betulinic acid attenuates lipopolysaccharide-induced vascular hyporeactivity in the rat aorta by modulating Nrf2 antioxidative function, Inflammopharmacology 28 (2020) 165-174.
[143]	M.S. Ozcan, M. Savran, D. Kumbul Doguc, et al., Dexpanthenol ameliorates lipopolysaccharide-induced cardiovascular toxicity by regulating the IL-6/HIF1α/VEGF pathway, Heliyon 10 (2024), e24007.
[144]	L.A. Callahan, G.S. Supinski, Sepsis-induced myopathy, Crit. Care Med. 37 (2009) S354-S367.
[145]	Y Hou, M Pai, J Wu, et al., Protective effects of glutamine and leucine supplementation on sepsis-induced skeletal muscle injuries, Int. J. Mol. Sci. 22 (2021), 13003.
[146]	H.W. Hyatt, S.K. Powers, Mitochondrial dysfunction is a common denominator linking skeletal muscle wasting due to disease, aging, and prolonged inactivity, Antioxidants 10 (2021), 588.
[147]	R.E. Schmitt, A. Dasgupta, P.C. Arneson-Wissink, et al., Muscle stem cells contribute to long-term tissue repletion following surgical sepsis, J. Cachexia Sarcopenia Muscle 14 (2023) 1424-1440.
[148]	A. Mansilla-Rosello, J. Hernandez-Magdalena, M. Dominguez-Bastante, et al., A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in surgical patients with severe sepsis admitted to the intensive care unit, J. Pineal Res. 74 (2023), e12845.
[149]	A.K. Patidar, P. Khanna, L. Kashyap, et al., Utilization of NIRS monitor to compare the regional cerebral oxygen saturation between dexmedetomidine and propofol sedation in mechanically ventilated critically ill patients with sepsis- a prospective randomized control trial, J. Intensive Care Med. 40 (2025) 379-387.
[150]	S. Williams Roberson, S. Nwosu, E.M. Collar, et al. Association of vitamin C, thiamine, and hydrocortisone infusion with long-term cognitive, psychological, and functional outcomes in sepsis survivors: a secondary analysis of the vitamin C, thiamine, and steroids in sepsis randomized clinical trial. Jama Netw. Open 6 (2023), e230380.