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Updated: Jun 20, 2026

Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways
Zewen Jiang1, Ruyuan He2, Yujian Zhong1
1Department of Orthopedic Surgery, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China.
Background:
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.
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