Targeting DNA Fragment Extrusion: A New Therapeutic Avenue for CCL4-Induced Hepatic Injury

Liver injury constitutes a significant threat to human health. The carbon tetrachloride (CCL₄)-induced liver injury model is the most extensively utilized animal model. For the first time, in situ hybridization chain reaction (HCR) was utilized to clearly provide morphological evidence of the extrusion of mitochondrial DNA fragments and numerous DNA fragments from apoptotic or necrotic hepatocytes induced by CCL₄. The expression of heat shock protein 60 (HSP60) in hepatocytes within CCL₄-induced liver injury tissue suggests that these cells are either undergoing or have undergone apoptosis or cell death, indicating that HSP60 may serve as a biomarker in this model. The in situ HCR and HSP60 immunofluorescence demonstrate superiority over the TUNEL assay in detecting early-stage apoptotic or necrotic hepatocytes. NIM811 significantly inhibits CCL₄-induced hepatocyte apoptosis or necrosis, the extrusion of DNA fragments, the activation of the cGAS-STING pathway, the expression of TNF-α and IL-6, as well as the fibrogenesis following liver injury. These findings suggest that inhibiting the extrusion of DNA fragments may represent a potential therapeutic strategy for liver injury.