Gallbladder removal induces hepatic transcriptional and metabolic shifts with cholesterol dysregulation as a key feature.

The gallbladder, traditionally viewed as a digestive accessory organ for bile storage and concentration, has recently been implicated in post-injury liver recovery. Yet, the underlying pathophysiological mechanisms remain unclear. Here, we employed a cholecystectomized mouse model to investigate the systemic impact of gallbladder removal on the hepatic transcriptome and metabolome. Transcriptomic profiling revealed temporal shifts in liver responses: protein synthesis and processing pathways were activated 7 days post-cholecystectomy, while immune response activation and cholesterol metabolism dysregulation predominated by day 30. Parallel untargeted metabolomics identified 2,272 metabolites, with 111 and 125 significantly differentially expressed metabolites (DEMs) at days 7 and 30, respectively. The DEMs were primarily lipids and lipid-like molecules, as well as organoheterocyclic compounds. Integrated multi-omics analysis highlighted cholesterol metabolism as the most markedly altered pathway in the liver following cholecystectomy. Together, these results demonstrate the broad transcriptional and metabolic reshaping of the liver after gallbladder removal and position cholesterol homeostasis as a key mechanistic candidate in cholecystectomy-associated hepatic pathophysiology. Our findings provide new molecular insights into post-cholecystectomy liver adaptation and offer a foundation for future therapeutic strategies targeting related metabolic disorders.