Qushi huayu decoction dose-dependent inhibition of caspase-2/SREBP-1 in MASLD mice.

Abstract

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is characterized by hepatic lipid accumulation and metabolic disturbances. Caspase-2 cleaves site-1 protease (S1P), leading to the persistent activation of sterol regulatory element-binding proteins (SREBPs), which subsequently promote the progression of MASLD. Previous studies have demonstrated that the Qushi Huayu Decoction (QHD) significantly alleviates MASLD, particularly inhibiting the expression of SREBP-1 in hepatocytes of MASLD mouse models. However, its regulatory effect on the Caspase-2/SREBP-1 pathway and the dose-dependent nature of these effects remain unclear.

Objective: The regulatory effects of high, medium, and low doses of Qushi Huayu Decoction (QHD) on the Caspase-2/SREBP-1 pathway and their potential dose-dependent impacts was investigated.

Method: A MASLD model was induced in 28-week-old C57BL/6J mice using a high-fat diet (HFD). Mice were treated with QHD granules at high (3.466 g/kg), medium (1.733 g/kg), and low doses (0.867 g/kg), as well as a Caspase-2 inhibitor for a duration of 5 weeks. Pharmacodynamic indicators, including triglycerides (TG) and free fatty acids (FFA) in liver tissue, hepatic histopathology, and serum biochemical markers, were assessed. The expression of genes in the Caspase-2/SREBP-1 signaling pathway and its downstream targets was also analyzed.

Results: QHD at all doses effectively improved hepatic steatosis. The low-dose group significantly reduced hepatic TG levels (p < 0.01) and the insulin resistance index (p < 0.05). The high-dose group significantly inhibited the expression of Caspase-2 protein (p < 0.01) and nuclear SREBP-1 protein (p < 0.05), with a dose-dependent decrease in Caspase-2 activity.

Conclusion: QHD exhibits dose-dependent, complementary effects in MASLD, with low doses improving lipid metabolism and insulin sensitivity, and high doses more effectively suppressing Caspase-2/SREBP-1 and inflammatory signaling. This dual action underscores its broad regulation of ER stress and supports stage-specific, hierarchical dosing strategies aligned with traditional Chinese medicine principles.