*Purpose: Acetaminophen (APAP) could cause liver injury, or even acute liver failure, accounting for approximately one-half of all cases in developed countries. Once acute liver failure occurs, liver transplantation becomes the only effective remedy, which has attracted extensive attention in the public health. However, there is still little known regarding the role of lncRNA on the regulation of disease development. This study aimed to investigate the expression profile of lncRNA in liver tissue in acetaminophen-induced liver injury (AILI) mouse model, and explore their roles using lncRNA-mRNA co-expression analysis.

*Methods: APAP 300mg/kg was used for establishing the stable AILI mouse model. Mice were sacrificed at 6h and 24h after APAP administration, and fresh liver tissues were collected for histopathology evaluation and whole RNA extraction. High-throughput RNA sequencing were performed to investigate the expression profile of mRNA and lncRNA. Differential expressed genes (DEGs) were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment annotation. The co-expression relationship between differentially expressed lncRNAs and mRNAs were delineated by co-expression network by Cytoscape. Some differential expressed mRNAs and lncRNAs were selected for RT-PCR validation, and the conservation of lncRNA between human and mouse was also analyzed.

*Results: Alanine aminotransferase and aspartate aminotransferase levels increased dramatically in the AILI mouse model. The histopathology of liver tissue presented as gross necrosis of the centrilobular areas, and 24h was more serious than 6h. RNA sequencing data revealed 1186 DEGs and 403 differential lncRNAs between 6h and 0h, 927 DEGs and 491 differential lncRNAs between 24h and 0h, and 323 DEGs and 4 differential lncRNAs between 24h and 6h (fold change ≥2, or ≤0.5, corrected P value<0.05), respectively. The mRNAs co-expressed with the differential lncRNAs in 24h vs. 6h were mainly enriched in the endoplasmic reticulum protein synthesis, MAPK signaling pathway, and PPAR signaling pathway. The lncRNA-mRNA co-expression network was delineated containing 4 lncRNAs and 94 mRNAs (Pearson correlation coefficient≥0.9, p<0.01), which could visually observe core position of lncRNA in the network. Validated by RT-PCR, the expression levels of selected mRNAs and lncRNAs were generally consistent with RNA-seq data. Conservation analysis indicated that four differential mouse lncRNAs (NONMMUT023651.2, NONMMUT029382.2, NONMMUT029383.2 and NONMMU5102053.1) could all be mapped to the relevant human lncRNAs.

*Conclusions: In summary, this is the first study to enrich the AILI lncRNA expression profile and 4 lncRNAs, NONMMUT023651.2, NONMMUT029382.2, NONMMUT029383.2 and NONMMU5102053.1 may play regulatory role through metabolic and apoptosis related pathways during hepatic homeostasis maintenance and repair progress.

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