Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP

Mitochondrial metabolism and innate immune signaling are increasingly recognized as intersecting pathways in chronic inflammatory disease. Here, we identify a metabolically driven mechanism linking the TCA cycle imbalance to mucosal inflammation in oral lichen planus (OLP). Multi-omics analysis revealed that fumarate hydratase (FH) is upregulated in OLP tissues and cells, leading to significant fumarate depletion. This metabolic shift induces mitochondrial dysfunction, characterized by enhanced oxidative phosphorylation, proton leak, and TFAM downregulation. These changes destabilize the mitochondrial genome, promote mtDNA leakage into the cytosol, and activate the cGAS-STING pathway, resulting in TBK1-IRF3- NF-κB -driven inflammatory responses. Genetic knockdown of FH or pharmacological supplementation with monomethyl fumarate (MMF) restored mitochondrial homeostasis, prevented mtDNA release, and attenuated immune activation. Furthermore, depletion of mtDNA using 2',3'-dideoxycytidine (ddC) validated the essential role of mtDNA in sustaining cGAS-STING dependent inflammation. Co-treatment with fumarate further suppressed cytosolic mtDNA and enhanced repression of innate signaling. These findings uncover a functional FH-fumarate-mtDNA-cGAS-STING axis in OLP and reveal fumarate as a key metabolic modulator of mitochondrial immune surveillance. Our work provides conceptual and therapeutic insight into the role of mitochondrial metabolism in non-infectious mucosal inflammation.