E2F3 Transcriptionally Induces YWHAE to Activate Hepatic Stellate Cells and Drives Non-Alcoholic Fatty Liver Disease Progression

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disorder characterized by excessive hepatic lipid accumulation and fibrosis.This study explores the molecular mechanism by which E2F transcription factor 3 (E2F3) transcriptionally activates 14-3-3 protein epsilon (YWHAE), promoting hepatic stellate cell (HSC) activation and contributing to NAFLD progression.Mice fed with a highfat diet showed significantly elevated YWHAE expression in liver tissues.YWHAE knockdown mitigated hepatic steatosis, reduced lipid deposition, and attenuated fibrosis, as confirmed by histological staining and Western blot analysis of fibrosis and lipogenesis markers.Additionally, an enzyme-linked immunosorbent assay indicated reduced serum levels of liver injury markers in YWHAE-deficient mice.In vitro, YWHAE knockdown in HSCs suppressed cell viability, migration, and activation, as assessed by cell counting kit-8, scratch assay, immunofluorescence, and RT-qPCR.Mechanistically, chromatin immunoprecipitation and luciferase reporter assays demonstrated that E2F3 bound to and enhanced YWHAE promoter activity, increasing its transcription.Furthermore, E2F3-mediated YWHAE activation promoted HSC activation and exacerbated NAFLD progression in vivo.These findings suggest that the E2F3-YWHAE axis may serve as a potential target for NAFLD treatment.