Annexin A2 Is Associated with Dietary Cholesterol-Induced Metabolic Dysregulation and the Progression of Hepatic Fibrosis

Background/Objectives: Dietary Cholesterol intake significantly influences liver health, yet the specific molecular mechanisms by which it accelerates fibrogenesis remain incompletely defined. This study aimed to characterize the dose-dependent effects of dietary Cholesterol on hepatic injury and fibrogenesis, identify cholesterol-responsive gene networks through transcriptomic analysis, and investigate Annexin A2 (AnxA2) as a candidate molecular mediator linking dietary Cholesterol to hepatic fibrosis progression. Methods: A CCl₄-induced liver fibrosis mouse model was established and supplemented with dietary Cholesterol (1-2%). Liver injury and fibrosis were assessed by liver-to-body weight ratios, serum biochemical markers, histological analysis, and fibrogenic gene expression. RNA Sequencing combined with multiple hepatic fibrosis database analyses was performed to identify potential molecular mediators. Results: Dietary Cholesterol supplementation aggravated CCl₄-induced hepatic fibrosis in mice, with dose-dependent increases in liver-to-body weight ratios and serum AST and ALT levels. Histological analysis showed enhanced Collagen deposition and upregulation of fibrogenic genes. By integrating RNA-sequencing with multiple hepatic fibrosis database analysis and correlation analysis, we identified Annexin A2 (AnxA2) as a cholesterol-responsive gene associated with fibrosis. Conclusions: Dietary Cholesterol promotes liver fibrosis progression, and AnxA2 may act as a potential mediator linking Cholesterol metabolism to hepatic fibrogenesis.