LKB1/ AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene.

Occupational medication-like dermatitis induced by trichloroethylene (OMDT) is a severe systemic allergic disease, often accompanied by acute liver injury. However, the underlying mechanisms linking metabolic disorders and immune damage remain unclear. In a TCE-sensitized mouse model, we demonstrated that TCE sensitization inhibited LKB1/AMPK/mTOR signaling pathway (LKB1 overexpression, AICAR, rapamycin) or autophagy (3-MA) in hepatocytes, resulting in defective mitophagy. This mitochondrial dysfunction leads to leakage of mitochondrial DNA (mtDNA) into the cytoplasm, where mtDNA acts as a damage-associated molecular pattern (DAMP) to activate the cGAS-STING pathway, driving the production of proinflammatory cytokines (IL-1β, IL-6, TNF-α), and exacerbating liver inflammation. Restoration of LKB1/AMPK signaling or inhibition of mTOR rescued mitophagi, reduced mitochondrial DNA leakage, inhibited cGAS-STING activation, and alleviated liver pathology, while inhibition of autophagy alone recapitulated the TCE-induced phenotype. Taken together, our findings demonstrate that failure of TCE via LKB1/AMPK/mTOR mediated mitophagy destroys hepatocyte homeostasis, leading to mtDNA-driven cGAS-STING activation and immune-mediated liver injury in the pathogenesis of OMDT, thus providing a potential therapeutic target for OMDT-related liver injury.