Elucidating Temporally Ordered Physiological Events During Liver Regeneration via Integrated Transcriptomic-Histological Profiling.

Although the liver possesses remarkable regenerative capacity, the detailed chronology spanning the pre-proliferative preparatory stage, hepatocyte proliferation, liver weight recovery, and the completion of molecular regeneration has not been fully elucidated. Using microarray-guided histological validation, we investigated the temporally ordered physiological events underlying liver regeneration following 70% partial hepatectomy (PH) in C57BL/6 mice. Our results demonstrated that PH induced multiple functional pathways, including the response to stilbenoid, steroid hormone metabolism, lipid transport, and angiogenesis. This was followed by activation of endoplasmic reticulum (ER) stress and insulin processing, accompanied by lipid accumulation, suppression of xenobiotic catabolic capacity, and altered circulating cholesterol levels. After recovery of these processes, hepatocytes and sinusoidal endothelial cells entered the proliferative phase. Notably, although liver weight had returned to preoperative levels, the transcriptome remained distinct from baseline, revealing divergence between macroscopic recovery and molecular-level convergence. At 336 h, two of three samples were assigned to the baseline Cluster 1, whereas one sample remained in Cluster 6 with a small number of altered genes. Together, these findings provide a detailed temporal framework in which metabolic and tissue remodeling during liver regeneration extends beyond macroscopic recovery.