ABSTRACT: Background: Liver regeneration (LR) after partial hepatectomy (PHx) involves complex molec-ular mechanisms, but the key regulatory networks remain incompletely understood. This study aims to characterize the multi-stage dynamics of LR after PHx and its core drivers. Methods: A PHx rat model was established for systematic assessment of histologic changes and serum biomarkers during regeneration. Transcriptomic analysis of liver tissues on the third day after PHx was performed to identify differentially expressed genes (DEGs). Moreover, the functions of key hub genes (Dcn and Hif1a) were verified by in vitro experiments, including the use of over-expression/knockdown plasmids, H2O2-induced hepatocyte injury model, and HIF1A inhibitor (LW6). Results: PHx triggered time-dependent inflammation, hepatocyte proliferation, and liver tissue remodeling. After the PHx procedure, the early phase was dominated by inflammation-driven and cellular proliferation, with a shift to liver tissue remodeling and functional recovery in the mid- to late phase. Transcriptomics identified 8,392 DEGs that were enriched in proliferation, autophagy, oxidative stress, apoptosis, inflammation, and metabolic reprogramming. Interaction analyses highlighted a critical sub-network consisting of 44 genes that regulate angiogenesis, LR, autophagy, and growth factor activity, including Dcn and Hif1a. In in vitro experiments, Dcn overexpression alleviated H2O2-induced BRL cell damage, including cell activity, cycle, autophagy, and oxidative stress. Dcn knockdown exhibited the opposite regulatory pattern. Mechanistically, Dcn upregulated HIF1A, and LW6-mediated HIF1A inhibition reversed the protective effect of Dcn on H2O2-induced hepatocyte injury. Conclusion: Dcn modulates hepatocyte proliferation, apoptosis, autophagy and oxidative stress through upregulating HIF1A, thereby alleviating hepatocyte injury. These findings reveal that the Dcn/HIF1A axis is a key therapeutic target for LR after PHx.
