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Despite numerous studies addressing normal liver regeneration, we still lack comprehensive understanding of the biological processes underlying failed liver regeneration. Therefore, we analyzed the activity of 271 intracellular signaling pathways (ISPs) by genome wide profiling of differentially expressed RNAs in murine liver tissue biopsies after normal hepatectomy (nHx; 68% of liver removed) and extended hepatectomy (eHx; 86% of liver removed). Comprehensive, genome-wide transcriptome profiling using RNAseq was performed in liver tissue obtained from mice (sham, nHx, and eHx) harvested 1, 8, 16, 32, and 48 h after operation (n = 3 per group) and the OncoFinder toolkit was used for an unsupervised, unbiased identification of intracellular signaling pathways (ISP) activity. We observed that the normal regenerative process requires a transient activation and silencing of approximately two dozen of ISPs. After nHx, the <i>Akt Pathway</i> represented with 13 branches, the <i>Chromatin Pathway</i> and the <i>DDR Pathways</i> dominated. After eHx, the <i>ATM main pathway</i> and two of its branches (<i>Cell Survival</i>; <i>G2_M Checkpoint Arrest</i>) dominated, as well as the <i>Hypoxia Pathways</i>. Further, 14 ISPs demonstrated a strong inverse regulation, with the <i>Hedgehog</i> and the <i>Brca1 Main Pathways</i> as chief activators after nHx, and the <i>ATM Pathway</i>(<i>G2_M Checkpoint Arrest</i>) as the dominating constraining response after eHx.