收稿日期: 2026-04-22
网络出版日期: 2026-08-05
基金资助
国家自然科学基金项目(82460375);国家自然科学基金项目(81960361);贵州省科技支撑项目[编号:黔科合支撑(2025)一般121];贵州省基础研究计划项目(编号:黔科合基础-ZK[2024]一般341);贵州省研究生创新计划(2024YJSKYJJ323);贵州省卫生健康委科学技术基金项目(gzwkj2025-011);贵州省卫生健康委科学技术基金项目(gzwkj2025-015);贵州省卫生健康委科学技术基金项目(gzwkj2025-208);珠海市社会发展领域科技计划项目(2420004000300);珠海市社会发展领域科技计划项目(2420004000107)
Research progress on the mechanism and treatment of glycolytic metabolic reprogramming in septic acute kidney injury
Received date: 2026-04-22
Online published: 2026-08-05
苟佳佳 , 田梓佑 , 李竹 , 唐立丽 , 张弓 , 何东蕊 , 李小悦 . 糖酵解代谢重编程在脓毒症急性肾损伤中的作用机制及治疗研究进展[J]. 实用医学杂志, 2026 , 42(14) : 2657 -2664 . DOI: 10.3969/j.issn.1006-5725.2026.14.019
Septic acute kidney injury (SAKI), a common and severe complication among sepsis patients, is characterized by a complex pathogenesis, a high morbidity rate, and a high mortality rate. In recent years, the role of metabolic reprogramming in the onset and development of diseases has drawn growing attention. As a crucial part of metabolic reprogramming, glycolytic metabolic reprogramming plays a significant role in the development and advancement of SAKI. This article reviews the research progress regarding the concept of glycolytic metabolic reprogramming, the mechanisms behind glycolytic metabolic reprogramming in SAKI, its regulatory impacts on SAKI, and SAKI treatment strategies based on glycolytic metabolic reprogramming. The purpose of this review is to thoroughly explore the pathogenesis of SAKI and offer potential targets for its clinical treatment.
| [1] | GóMEZ H, KELLUM J A. Sepsis-induced acute kidney injury [J]. Curr Opin Crit Care, 2016, 22(6): 546-553.doi:10.1097/mcc.0000000000000356 . |
| [2] | PEERAPORNRATANA S, MANRIQUE-CABALLERO C L, GóMEZ H, et al. Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment [J]. Kidney Int, 2019, 96(5): 1083-1099.doi:10.1016/j.kint.2019.05.026 . |
| [3] | SEE E J, JAYASINGHE K, GLASSFORD N, et al. Long-term risk of adverse outcomes after acute kidney injury: A systematic review and meta-analysis of cohort studies using consensus definitions of exposure [J]. Kidney Int, 2019, 95(1): 160-172.doi:10.1016/j.kint.2018.08.036 . |
| [4] | 康凌垲,李小悦,张倩. 脓毒症相关急性肾损伤发病机制和新型生物标志物研究进展[J]. 实用医学杂志, 2021, 37(6):705-708.doi:10.3969/j.issn. 1006- 5725.2021.06.002 . |
| [5] | POSTON J T, KOYNER J L. Sepsis associated acute kidney injury [J]. BMJ, 2019, 364: k4891.doi:10.1136/bmj.k4891 . |
| [6] | WANG T, HUANG Y, ZHANG X, et al. Advances in metabolic reprogramming of renal tubular epithelial cells in sepsis-associated acute kidney injury [J]. Front Physiol, 2024, 15: 1329644.doi:10.3389/fphys. 2024. 1329644 . |
| [7] | 孙学梦, 刘芳远, 苏丽娅. 代谢重编程在恶性肿瘤中作用的研究进展 [J]. 中国肿瘤生物治疗杂志, 2023, 30(5): 432-437.doi: 10.3872/j.issn.1007-385x. 2023.05.009 . |
| [8] | 陈惠, 乔瑞, 韩萌, 等. 肿瘤中糖代谢重编程的研究进展 [J]. 宁夏医科大学学报, 2022, 44(11): 1170-1175.doi:10.16050/j.cnki.issn1674-6309.2022.11. 017 . |
| [9] | KOCIANOVA E, PIATRIKOVA V, GOLIAS T. Revisiting the Warburg Effect with Focus on Lactate [J]. Cancers (Basel), 2022, 14(24):6028.doi:10.3390/ cancers14246028 . |
| [10] | GóMEZ H, KELLUM J A, RONCO C. Metabolic reprogramming and tolerance during sepsis-induced AKI [J]. Nat Rev Nephrol, 2017, 13(3): 143-151.doi:10.1038/nrneph.2016.186 . |
| [11] | LIU C, WEI W, HUANG Y, et al. Metabolic reprogramming in septic acute kidney injury: Pathogenesis and therapeutic implications [J]. Metabolism, 2024, 158: 155974.doi:10.1016/j.metabol.2024.155974 . |
| [12] | BHARGAVA P, SCHNELLMANN R G. Mitochondrial energetics in the kidney [J]. Nat Rev Nephrol, 2017, 13(10): 629-646.doi:10.1038 /nrneph.2017. 107 . |
| [13] | CHENG C J, NIZAR J M, DAI D F, et al. Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules [J]. Faseb J, 2024, 38(10): e23703.doi:10.1096/fj.202400358RR . |
| [14] | LI Z, LU S, LI X. The role of metabolic reprogramming in tubular epithelial cells during the progression of acute kidney injury [J]. Cell Mol Life Sci, 2021, 78(15): 5731-5741.doi:10.1007/s00018-021-03892-w . |
| [15] | BAKKER J, POSTELNICU R, MUKHERJEE V. Lactate: Where Are We Now [J]. Crit Care Clin, 2020, 36(1): 115-124.doi:10.1016/j.ccc.2019.08.009 . |
| [16] | LUO M, MI Z, YU B, et al. LDHB K156 lactylation links cGAS-STING-mediated metabolic reprogramming to NLRP3 inflammasome activation in sepsis-associated acute kidney injury [J]. Life Sci, 2026, 392: 124311.doi:10.1016/j.lfs.2026.124311 . |
| [17] | YANG K, FAN M, WANG X, et al. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis [J]. Cell Death Differ, 2022, 29(1): 133-146.doi:10.1038/s41418-021-00841-9 . |
| [18] | DE JESUS A, KEYHANI-NEJAD F, PUSEC C M, et al. Hexokinase 1 cellular localization regulates the metabolic fate of glucose [J]. Mol Cell, 2022, 82(7): 1261-1277.e1269.doi:10.1016/j.molcel.2022.02.028 . |
| [19] | ALQURAISHI M, PUCKETT D L, ALANI D S, et al. Pyruvate kinase M2: A simple molecule with complex functions [J]. Free Radic Biol Med, 2019, 143: 176-192.doi:10.1016/j.freeradbiomed.2019.08.007 . |
| [20] | KELLY B, O'NEILL L A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity [J]. Cell Res, 2015, 25(7): 771-784.doi:10.1038/cr.2015.68 . |
| [21] | MILLS E L, KELLY B, LOGAN A, et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages [J]. Cell, 2016, 167(2): 457-470.e413.doi:10.1016/j.cell.2016.08.064 . |
| [22] | 蔡兴, 马兴龙, 周长健, 等. 巨噬细胞糖酵解在脓毒症中的研究进展[J]. 实用医学杂志, 2024, 40(19): 2783-2788. doi:10.3969/j.issn.1006- 5725. 2024.19.020 . |
| [23] | XIAN D, CHEN F, LIU B, et al. Metabolic reprogramming tailors T cell immunity in sepsis [J]. Front Immunol, 2025, 16: 1679493.doi: 10.3389/ fimmu.2025.1679493 . |
| [24] | LELIEFELD P H, KOENDERMAN L, PILLAY J. How Neutrophils Shape Adaptive Immune Responses [J]. Front Immunol, 2015, 6: 471.doi:10.3389/ fimmu.2015.00471 . |
| [25] | AWASTHI D, NAGARKOTI S, KUMAR A, et al. Oxidized LDL induced extracellular trap formation in human neutrophils via TLR-PKC-IRAK-MAPK and NADPH-oxidase activation [J]. Free Radic Biol Med, 2016, 93: 190-203.doi:10.1016/j.freeradbiomed.2016.01.004 . |
| [26] | KUANG X, NIU Z, HUANG Z, et al. GDF15 attenuates sepsis-induced acute lung injury by suppressing the HIF-1α/LDHA pathway [J]. Int Immunopharmacol, 2025, 163: 115198.doi:10.1016/j.intimp.2025.115198 . |
| [27] | YU B, SHEN K, LI T, et al. Glycolytic enzyme PFKFB3 regulates sphingosine 1-phosphate receptor 1 in proangiogenic glomerular endothelial cells under diabetic condition [J]. Am J Physiol Cell Physiol, 2023, 325(5): C1354-c1368.doi:10.1152/ajpcell.00261.2023 . |
| [28] | JIA P, XU S, WANG X, et al. Chemokine CCL2 from proximal tubular epithelial cells contributes to sepsis-induced acute kidney injury [J]. Am J Physiol Renal Physiol, 2022, 323(2): F107-f119.doi:10.1152/ ajprenal. 00037.2022 . |
| [29] | MIGUEL V, SHAW I W, KRAMANN R. Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease [J]. Nat Rev Nephrol, 2025, 21(1): 39-56.doi:10.1038/s41581-024-00889-z . |
| [30] | LIANG H, XU L, YANG Y. Lactate and lactylation: Novel perspectives on fibrosis pathogenesis and therapeutic directions [J]. J Transl Med, 2025, 23(1): 705.doi:10.1186/s12967-025-06748-0 . |
| [31] | BROMBACHER E C, PATENTE T A, VAN DER HAM A J, et al. AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism [J]. J Cell Biol, 2024, 223(10).doi:10.1083/jcb. 202401024 . |
| [32] | YANG Y Y, GONG D J, ZHANG J J, et al. Diabetes aggravates renal ischemia-reperfusion injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy [J]. Am J Physiol Renal Physiol, 2019, 317(4): F852-f864.doi:10.1152/ajprenal.00181.2019 . |
| [33] | YE L, JIANG Y, ZHANG M. Crosstalk between glucose metabolism, lactate production and immune response modulation [J]. Cytokine Growth Factor Rev, 2022, 68: 81-92.doi:10.1016/j.cytogfr.2022.11.001 . |
| [34] | DONG Q, YANG X, WANG L, et al. Lactylation of Hdac1 regulated by Ldh prevents the pluripotent-to-2C state conversion [J]. Stem Cell Res Ther, 2024, 15(1): 415.doi:10.1186/s13287-024-04027-1 . |
| [35] | CORCORAN S E, O'NEILL L A. HIF1α and metabolic reprogramming in inflammation [J]. J Clin Invest, 2016, 126(10): 3699-3707.doi: 10.1172/ jci84431 . |
| [36] | TANNAHILL G M, CURTIS A M, ADAMIK J, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α [J]. Nature, 2013, 496(7444): 238-242.doi:10.1038/nature11986 . |
| [37] | SAXTON R A, SABATINI D M. mTOR Signaling in Growth, Metabolism, and Disease [J]. Cell, 2017, 169(2): 361-371.doi:10.1016/j.cell.2017.03.035 . |
| [38] | PAN T, SUN S, 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.doi:10.1186/s13054-022-03893-6 . |
| [39] | KE R, XU Q, LI C, et al. Mechanisms of AMPK in the maintenance of ATP balance during energy metabolism [J]. Cell Biol Int, 2018, 42(4): 384-392.doi:10.1002/cbin.10915 . |
| [40] | HERZIG S, SHAW R J. AMPK: guardian of metabolism and mitochondrial homeostasis [J]. Nat Rev Mol Cell Biol, 2018, 19(2): 121-135.doi:10.1038/ nrm.2017.95 . |
| [41] | TORO J, MANRIQUE-CABALLERO C L, GóMEZ H. Metabolic Reprogramming and Host Tolerance: A Novel Concept to Understand Sepsis-Associated AKI [J]. J Clin Med, 2021, 10(18).doi:10.3390/jcm 10184184 . |
| [42] | ZHANG Z, DENG X, LIU Y, et al. PKM2, function and expression and regulation [J]. Cell Biosci, 2019, 9: 52.doi:10.1186/s13578-019-0317-8 . |
| [43] | XIAO M, LIU D, XU Y, et al. Role of PFKFB3-driven glycolysis in sepsis [J]. Ann Med, 2023, 55(1): 1278-1289.doi:10.1080/07853890.2023.2191217 . |
| [44] | TIAN W, GUO H S, LI C Y, et al. PFKFB3 promotes endotoxemia-induced myocardial dysfunction through inflammatory signaling and apoptotic induction [J]. Toxicol Appl Pharmacol, 2019, 368: 26-36.doi:10.1016/ j.taap. 2019.02.007 . |
| [45] | YI Z, WU Y, ZHANG W, et al. Activator-Mediated Pyruvate Kinase M2 Activation Contributes to Endotoxin Tolerance by Promoting Mitochondrial Biogenesis [J]. Front Immunol, 2020, 11: 595316.doi:10.3389/fimmu. 2020. 595316 . |
| [46] | BROOKS G A. The Science and Translation of Lactate Shuttle Theory [J]. Cell Metab, 2018, 27(4): 757-785.doi:10.1016/j.cmet.2018.03.008 . |
| [47] | TAN C, 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).doi:10.3892 /ijmm.2021.4852 . |
| [48] | AN S, YAO Y, HU H, et al. PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation [J]. Cell Death Dis, 2023, 14(7): 457.doi:10.1038/ s41419- 023-05952-4 . |
| [49] | DING H, ZHOU Y, ZHU R H, et al. HIF-1-mediated macrophage metabolic reprogramming promotes AKI to CKD transition [J]. Int J Biol Sci, 2025, 21(13): 5936-5955.doi:10.7150/ijbs.111238 . |
| [50] | TRAN T A T, IWATA Y, HOANG L T, et al. Protective Role of MAVS Signaling for Murine Lipopolysaccharide-Induced Acute Kidney Injury [J]. Immunohorizons, 2024, 8(1): 1-18.doi:10.4049/immunohorizons.2300069 . |
| [51] | HUANG W L, WANG Y C, CHENG T L, et al. Histone Lactylation-Mediated PAD4 Up-Regulation Promotes Septic Acute Kidney Injury via Activating NETosis [J]. Nephrology (Carlton), 2025, 30(10): e70137.doi:10.1111/ nep. 70137 . |
| [52] | QIAO J, TAN Y, LIU H, et al. Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis-Associated Acute Kidney Injury [J]. Adv Sci (Weinh), 2024, 11(28): e2307216.doi:10.1002/advs.202307216 . |
| [53] | LI H, LIU C, LI R, et al. AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases [J]. Nature, 2024, 634(8036): 1229-1237.doi:10.1038/s41586-024-07992-y . |
| [54] | SCH?DEL J, RATCLIFFE P J. Mechanisms of hypoxia signalling: New implications for nephrology [J]. Nat Rev Nephrol, 2019, 15(10): 641-659.doi: 10.1038/s41581-019-0182-z . |
| [55] | ZHANG S, LUO M, LU Z, et al. Lactate and lactylation in sepsis-associated acute kidney injury: Clinical evidence from the MIMIC-IV database and mechanistic insights [J]. Front Med (Lausanne), 2025, 12: 1708145.doi: 10.3389/fmed.2025. 1708145 . |
| [56] | SARAIVA I E, HAMAHATA N, HUANG D T, et al. Metformin for sepsis-associated AKI: A protocol for the Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI) [J]. BMJ Open, 2024, 14(4): e081120.doi:10.1136/ bmjopen- 2023-081120 . |
| [57] | VAN MOORTER N, TACKAERT T, DE DECKER K, et al. New potential for an old kid on the block: Impact of premorbid metformin use on lactate kinetics, kidney injury and mortality in sepsis and septic shock, an observational study [J]. Endocrinol Diabetes Metab, 2023, 6(1): e382.doi:10.1002/edm2.382 . |
| [58] | FUNAHASHI Y, PARK S H, HEBERT J F, et al. Nanotherapeutic kidney cell-specific targeting to ameliorate acute kidney injury [J]. Kidney Int, 2024, 106(4): 597-610.doi:10.1016/j.kint. 2024.06.021 . |
/
| 〈 |
|
〉 |