ScRNA-seq combined with ATAC-seq analysis to explore the metabolic balance mechanism of CCl4-induced liver inflammatory injury.

Background: Drug-induced liver injury (DILI) can provoke inflammation and fibrosis in the liver, potentially leading to severe liver diseases and mortality; however, effective treatments for liver fibrosis remain elusive. The objective of this study was to explore the cellular metabolic mechanism after carbon tetrachloride (CCl4)-induced liver injury. Methods: Initially, we conducted a comprehensive analysis of ATAC-seq, RNA-seq, and scRNA-seq datasets derived from CCl4-induced chronic liver injury in mice. Subsequently, functional enrichment analysis and transcription factor analysis were performed. Finally, the expression changes of key substances and transcription factors were verified by cell and animal experiments. Results: Our investigation uncovered that hepatocyte histone acetylation intensified with prolonged injury durations. Subsequent functional enrichment analysis identified that fatty acid metabolism as the predominant pathway implicated in hepatocyte damage. The tricarboxylic acid cycle in hepatocytes exhibited partial slowdown and the mitochondrial electron transport chain (ETC) was inhibited in the early stage of CCl4-induced chronic injury. However, in the later stage of injury, there was a gradual restoration of the ETC functionality, coupled with an enhanced capacity for Conclusion: Our findings contribute to the understanding of the evolution and underlying CCl4-induced inflammatory mechanisms governing hepatocyte inflammatory injury and the subsequent metabolic shift from imbalance toward balance under chronic CCl4 exposure, offering novel perspectives and directions for targeted therapeutic interventions in DILI.