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The liver is a unique organ that has a phenomenal capacity to regenerate after injury. Different surgical procedures, including partial hepatectomy (PH), intraoperative portal vein ligation (PVL), and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) show clinically distinct recovery patterns and regeneration. The observable clinical differences likely mirror some underlying variations in the patterns of gene activation and regeneration pathways. In this study, we provided a comprehensive comparative transcriptomic analysis of gene regulation in regenerating rat livers temporally spaced at 24 h and 96 h after PH, PVL, and ALPPS. The time-dependent factors appear to be the most important determinant of post-injury alterations of gene expression in liver regeneration. Gene expression profile after ALPPS showed more similar expression pattern to the PH than the PVL at the early phase of the regeneration. Early transcriptomic changes and predicted upstream regulators that were found in all three procedures included cell cycle associated genes ( E2F1, CCND1, FOXM1, TP53 , and  RB1 ), transcription factors ( Myc, E2F1, TBX2, FOXM1 ), DNA replication regulators ( CDKN1A, EZH2, RRM2 ), G1/S-transition regulators ( CCNB1, CCND1, RABL6 ), cytokines and growth factors ( CSF2, IL-6, TNF, HGF, VEGF , and  EGF ), ATM and p53 signaling pathways. The functional pathway, upstream, and network analyses revealed both unique and overlapping molecular mechanisms and pathways for each surgical procedure. Identification of molecular signatures and regenerative signaling pathways for each surgical procedure further our understanding of key regulators of liver regeneration as well as patient populations that are likely to benefit from each procedure.

RNA-Seq transcriptome profiling in three liver regeneration models in rats: comparative analysis of partial hepatectomy, ALLPS, and PVL