Hepatocyte-Specific RORα Deficiency Accelerates Liver Regeneration by Unleashing ME1-Driven Glycolysis

Background/Objectives: Hepatocyte proliferation during liver regeneration requires precise transcriptional coordination of metabolic reprogramming, but the key regulators governing this process remain largely unknown. Methods: Hepatocyte-specific retinoic acid receptor-related orphan receptor α (RORα) knockout (RORα-LKO) mice were generated and subjected to two-thirds partial hepatectomy (PHx). Liver regeneration was assessed by liver-to-body weight ratio, histology, and proliferation markers (PCNA, Ki67, cyclin D1). Metabolic changes were evaluated by untargeted metabolomics, Seahorse extracellular flux analysis, and glycolytic enzyme activity assays. The molecular mechanism was investigated through RNA-seq analysis, qPCR, Western blotting, dual-luciferase reporter assays, CUT&Tag-qPCR, and pharmacological inhibition. Results: RORα expression was transiently upregulated during the early phase and declined at the peak of hepatocyte proliferation. RORα-LKO mice exhibited accelerated liver recovery and increased hepatocyte proliferation following a partial hepatectomy, without enhanced inflammation or fatty acid oxidation. Mechanistically, RORα directly binds to the promoter of Me1 to repress its transcription. Loss of RORα upregulates ME1, enhances glycolysis, and increases ATP production. Pharmacological inhibition of ME1 reversed these effects. Conclusions: The RORα–ME1 axis links transcriptional repression to metabolic reprogramming and may represent a therapeutic target for liver regeneration.