Micheliolide attenuates sepsis-induced acute lung injury by suppressing mitochondrial oxidative stress and PFKFB3-driven glycolysis.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Glycolysis*/drug effects ; Sepsis*/complications ; Sepsis*/drug therapy ; Oxidative Stress*/drug effects ; Acute Lung Injury*/drug therapy ; Acute Lung Injury*/pathology ; Acute Lung Injury*/etiology ; Mitochondria*/metabolism ; Mitochondria*/drug effects ; Phosphofructokinase-2*/metabolism ; Mice, Inbred C57BL*; Animals ; Mice ; RAW 264.7 Cells ; Male ; Sesquiterpenes, Guaiane/pharmacology ; Macrophages/metabolism ; Macrophages/drug effects ; Lipopolysaccharides ; Inflammation/pathology

Background: Sepsis is a potentially fatal condition with a significant risk of death. Acute lung injury (ALI) is a life-threatening complication of sepsis, and the inflammatory response plays a critical role in sepsis-induced ALI. The protective effects of micheliolide (MCL) against renal fibrosis and leukemia have been demonstrated, but the precise underlying mechanisms remain unclear.
Methods: In vitro, lipopolysaccharides (LPS) and interferon-gamma (IFN-γ) were used to stimulate RAW264.7 cells and bone marrow-derived macrophages (BMDMs) to investigate the protective effect of MCL on sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in mice to induce ALI in vivo. The expression of inflammatory factors, macrophage polarization markers, and the glycolysis-related enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were measured in vivo. Mitochondrial function, oxidative stress, and mitochondrial-related proteins were evaluated in vitro.
Results: MCL inhibited CLP-induced ALI, as evidenced by improvements in proinflammatory factor levels, lung wet/dry ratios, and histopathological findings. In vitro, MCL treatment significantly suppressed LPS + IFN-γ-induced M1-type polarization of RAW264.7 cells and BMDMs, as well as the production of inflammatory factors and oxidative stress. Mechanistic experiments revealed that MCL suppresses PFKFB3-driven glycolysis to reduce inflammation and activates the mitochondrial unfolded protein response (UPR ^mt ) to alleviate mitochondrial stress. However, the therapeutic effect of MCL was diminished when PFKFB3 was overexpressed in cells.
Conclusion: This study is the first to demonstrate that MCL attenuates sepsis-induced ALI by reducing M1-type macrophage polarization. Its therapeutic effect is closely related to the suppression of oxidative stress and PFKFB3-driven glycolysis.
Competing Interests: Declarations. Ethics approval and consent to participate: All mice experiments were approved by the Southern Medical University Committee on Ethics of Animal Experiments (application NO: IACUC-LAC-20230705–001). Competing interests: The authors declare that they have no competing interests.
(© 2025. The Author(s).)

Angiogenesis. 2020 Aug;23(3):299-314. (PMID: 32246225)
Cancer Res. 2020 Mar 1;80(5):937-949. (PMID: 31862780)
PLoS One. 2014 Sep 16;9(9):e107181. (PMID: 25226033)
ACS Cent Sci. 2021 May 26;7(5):841-857. (PMID: 34079900)
Acta Pharm Sin B. 2023 Dec;13(12):4785-4800. (PMID: 38045056)
J Med Chem. 2018 May 10;61(9):4155-4164. (PMID: 29641204)
Crit Care. 2022 Jan 28;26(1):29. (PMID: 35090526)
Nutrients. 2021 Dec 24;14(1):. (PMID: 35010945)
Redox Biol. 2022 Aug;54:102351. (PMID: 35671636)
J Ethnopharmacol. 2023 Jan 30;301:115781. (PMID: 36195302)
Nat Rev Endocrinol. 2022 Apr;18(4):243-258. (PMID: 35145250)
Redox Biol. 2024 Feb;69:102987. (PMID: 38100883)
Redox Biol. 2021 Sep;45:102049. (PMID: 34174558)
Crit Care Med. 2007 Nov;35(11):2538-46. (PMID: 17828034)
Front Immunol. 2020 Aug 04;11:1722. (PMID: 32849610)
Bioorg Chem. 2021 Jun;111:104973. (PMID: 34004586)
Nat Rev Cardiol. 2018 Sep;15(9):543-554. (PMID: 30042431)
Nature. 2013 Apr 11;496(7444):238-42. (PMID: 23535595)
Oxid Med Cell Longev. 2020 Apr 23;2020:9829176. (PMID: 32411336)
J Inflamm Res. 2022 Mar 30;15:2121-2139. (PMID: 35386222)
Signal Transduct Target Ther. 2022 Sep 1;7(1):303. (PMID: 36045132)
Heliyon. 2023 Jul 04;9(7):e17848. (PMID: 37456020)
Cell Mol Immunol. 2022 Apr;19(4):504-515. (PMID: 34983946)
Pharmacol Res. 2019 Aug;146:104292. (PMID: 31167111)
Antioxid Redox Signal. 2015 Jan 20;22(3):241-58. (PMID: 25089563)
Redox Biol. 2022 Oct;56:102446. (PMID: 36057161)
J Hematol Oncol. 2022 Jul 21;15(1):98. (PMID: 35864539)
Free Radic Biol Med. 2016 Nov;100:188-198. (PMID: 27387767)
Front Immunol. 2022 Jul 14;13:880286. (PMID: 35911719)
Cell Rep. 2021 Nov 2;37(5):109955. (PMID: 34731634)

82270089 National Natural Science Foundation of China; 81870068 National Natural Science Foundation of China; 202312121006 National College Students' Innovation and Entrepreneurship Training Program

Keywords: Acute lung injury; Glycolysis; Macrophage polarization; Oxidative stress; PFKFB3

EC 2.7.1.105 (Phosphofructokinase-2)
0 (micheliolide)
EC 2.7.1.105 (PFKFB3 protein, mouse)
0 (Sesquiterpenes, Guaiane)
0 (Lipopolysaccharides)

Date Created: 20250214 Date Completed: 20250215 Latest Revision: 20250218

20250218

PMC11829335

10.1186/s12967-024-05906-0

39953547