Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways.

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.