Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways
Year: 2025
Type: article
Abstract: 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 [email protected] Ziqi He, Department of Urology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Email [email protected]: 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
Authors: Jiang Z, He R, Zhong Y, Liu B, He Z
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6981984355
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