Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways
Zewen Jiang,1,* Ruyuan He,2,* Yujian Zhong,1,* Bohao Liu,3 Ziqi He4 1Department of Orthopedic Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of Chi...
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Dove Medical Press
2025-04-01
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| author | Jiang Z He R Zhong Y Liu B He Z |
| author_facet | Jiang Z He R Zhong Y Liu B He Z |
| author_sort | Jiang Z |
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| description | Zewen Jiang,1,* Ruyuan He,2,* Yujian Zhong,1,* Bohao Liu,3 Ziqi He4 1Department of Orthopedic Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, People’s Republic of China; 4Department of Urology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bohao Liu, Department of Thoracic Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Chaoyang District, Changchun, 130021, Jilin Province, People’s Republic of China, Email liubohao123@jlu.edu.cn Ziqi He, Department of Urology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Email zigihe1990@163.comBackground: The metabolic reprogramming of alveolar macrophages, particularly mitochondrial energy metabolism centered on the tricarboxylic acid (TCA) cycle, plays a pivotal role in acute lung injury (ALI). Fumarate hydratase (FH), a key enzyme catalyzing fumarate-to-malate conversion in the TCA cycle, is implicated in macrophage inflammatory responses, but its specific role in ALI remains unclear.Methods: We employed FHIN1 to assess its regulatory effects in LPS-induced ALI models. Wildtype C57BL/6 mice were randomly divided into control group, FHIN1 group, LPS group and LPS+FHIN1 group. FHIN1 and RU.521 was used to explored the interaction of FH and cGAS-STING in THP-1 cells.Results: LPS stimulation suppressed FH expression and induced fumarate accumulation in macrophages. Pharmacological FH inhibition exacerbated LPS-triggered inflammatory cytokine release, oxidative stress and aggravated lung injury in mice. Mechanistically, FH inhibition promoted mtDNA leakage, activating the cGAS-STING pathway to amplify inflammation. Blocking cGAS with RU.521 significantly attenuated FHIN1-driven inflammatory responses and mitigated lung injury exacerbation.Conclusion: FH critically modulates ALI progression by restraining cGAS-STING-dependent inflammation. Targeting the FH-mtDNA-cGAS axis may offer therapeutic potential for ALI management. Keywords: ALI, fumarate hydratase, mtDNA |
| format | Article |
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| publishDate | 2025-04-01 |
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| spelling | doaj-art-2c421ac709cb4ed19fa0c39f3815b28d2025-08-20T02:20:17ZengDove Medical PressJournal of Inflammation Research1178-70312025-04-01Volume 1853995413102269Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING PathwaysJiang ZHe RZhong YLiu BHe ZZewen Jiang,1,* Ruyuan He,2,* Yujian Zhong,1,* Bohao Liu,3 Ziqi He4 1Department of Orthopedic Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, People’s Republic of China; 4Department of Urology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bohao Liu, Department of Thoracic Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Chaoyang District, Changchun, 130021, Jilin Province, People’s Republic of China, Email liubohao123@jlu.edu.cn Ziqi He, Department of Urology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Email zigihe1990@163.comBackground: The metabolic reprogramming of alveolar macrophages, particularly mitochondrial energy metabolism centered on the tricarboxylic acid (TCA) cycle, plays a pivotal role in acute lung injury (ALI). Fumarate hydratase (FH), a key enzyme catalyzing fumarate-to-malate conversion in the TCA cycle, is implicated in macrophage inflammatory responses, but its specific role in ALI remains unclear.Methods: We employed FHIN1 to assess its regulatory effects in LPS-induced ALI models. Wildtype C57BL/6 mice were randomly divided into control group, FHIN1 group, LPS group and LPS+FHIN1 group. FHIN1 and RU.521 was used to explored the interaction of FH and cGAS-STING in THP-1 cells.Results: LPS stimulation suppressed FH expression and induced fumarate accumulation in macrophages. Pharmacological FH inhibition exacerbated LPS-triggered inflammatory cytokine release, oxidative stress and aggravated lung injury in mice. Mechanistically, FH inhibition promoted mtDNA leakage, activating the cGAS-STING pathway to amplify inflammation. Blocking cGAS with RU.521 significantly attenuated FHIN1-driven inflammatory responses and mitigated lung injury exacerbation.Conclusion: FH critically modulates ALI progression by restraining cGAS-STING-dependent inflammation. Targeting the FH-mtDNA-cGAS axis may offer therapeutic potential for ALI management. Keywords: ALI, fumarate hydratase, mtDNAhttps://www.dovepress.com/fumarate-hydratase-restrains-mtdna-attenuates-lps-induced-acute-lung-i-peer-reviewed-fulltext-article-JIRalifumarate hydratasemtdna |
| spellingShingle | Jiang Z He R Zhong Y Liu B He Z Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways Journal of Inflammation Research ali fumarate hydratase mtdna |
| title | Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways |
| title_full | Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways |
| title_fullStr | Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways |
| title_full_unstemmed | Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways |
| title_short | Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways |
| title_sort | fumarate hydratase restrains mtdna attenuates lps induced acute lung injury through cgas sting pathways |
| topic | ali fumarate hydratase mtdna |
| url | https://www.dovepress.com/fumarate-hydratase-restrains-mtdna-attenuates-lps-induced-acute-lung-i-peer-reviewed-fulltext-article-JIR |
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