Huangjing Jiangzhi Granules Ameliorate Nonalcoholic Fatty Liver Disease by Activating the FOXA1-DERL1 Regulatory Axis to Suppress Lipid Accumulation, Endoplasmic Reticulum Stress, and Apoptosis.

Nonalcoholic fatty liver disease (NAFLD) is an emerging health issue worldwide. It involves intrahepatic lipid accumulation that is potentially deleterious. Traditional Chinese Medicine called Huangjing Jiangzhi (HJJZ) granules holds promise for NAFLD treatment. This study explored the mechanism by which HJJZ granules improve NAFLD in male C57BL/6 mice and oleic acid-induced HepG2 cells.H&E staining, Oil Red O staining, the TUNEL assay, and Western blotting were employed. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to examine transcriptional regulation.HJJZ granules alleviated hepatic steatosis, reduced serum ALT/AST levels, improved lipid profiles, suppressed hepatocyte apoptosis, and inhibited the PERK-eIF2α-CHOP pathway in high-fat diet-fed mice and oleic acid-treated cells. These granules specifically upregulated the expression of the transcription factor FOXA1. FOXA1 knockdown abolished all protective effects of HJJZ granules. Mechanistically, FOXA1 was shown to transcriptionally activate DERL1 expression. DERL1 overexpression rescued the steatotic, apoptotic, and endoplasmic reticulum (ER) stress phenotypes in FOXA1-deficient cells.HJJZ granules ameliorate NAFLD by attenuating lipid accumulation, apoptosis, and ER stress. This protective effect is mediated through FOXA1 upregulation, which, in turn, transcriptionally enhances DERL1 expression, thereby mitigating ER stress. The FOXA1/DERL1 axis is a critical mechanistic pathway for HJJZ granule action.