Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting the PDGFRβ/PI3K/AKT pathway

Qian Meng; Hongwen Zhu; Yuanyuan Li; Xiaotian Peng; Tianming Wang; Hui Huang; Hu Zhou; Yuejia Liu; Sujie Ru; Jiasheng Wu; Yueming Ma

doi:10.3389/fphar.2024.1341020

Quantitative proteomics reveals the protective effects of Yinchenzhufu decoction against cholestatic liver fibrosis in mice by inhibiting the PDGFRβ/PI3K/AKT pathway

Front Pharmacol. 2024 Feb 26:15:1341020. doi: 10.3389/fphar.2024.1341020. eCollection 2024.

Authors

Qian Meng^{1

2}, Hongwen Zhu², Yuanyuan Li¹, Xiaotian Peng¹, Tianming Wang¹, Hui Huang², Hu Zhou^{2

3}, Yuejia Liu^{2

4}, Sujie Ru^{2

4}, Jiasheng Wu¹, Yueming Ma¹

Affiliations

¹ Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

Abstract

Introduction: Yinchenzhufu decoction (YCZFD) is a traditional Chinese medicine formula with hepatoprotective effects. In this study, the protective effects of YCZFD against cholestatic liver fibrosis (CLF) and its underlying mechanisms were evaluated. Methods: A 3, 5-diethoxycarbonyl-1, 4-dihydro-collidine (DDC)-induced cholestatic mouse model was used to investigate the amelioration of YCZFD on CLF. Data-independent acquisition-based mass spectrometry was performed to investigate proteomic changes in the livers of mice in three groups: control, model, and model treated with high-dose YCZFD. The effects of YCZFD on the expression of key proteins were confirmed in mice and cell models. Results: YCZFD significantly decreased the levels of serum biochemical, liver injury, and fibrosis indicators of cholestatic mice. The proteomics indicated that 460 differentially expressed proteins (DEPs) were identified among control, model, and model treated with high-dose YCZFD groups. Enrichment analyses of these DEPs revealed that YCZFD influenced multiple pathways, including PI3K-Akt, focal adhesion, ECM-receptor interaction, glutathione metabolism, and steroid biosynthesis pathways. The expression of platelet derived growth factor receptor beta (PDGFRβ), a receptor associated with the PI3K/AKT and focal adhesion pathways, was upregulated in the livers of cholestatic mice but downregulated by YCZFD. The effects of YCZFD on the expression of key proteins in the PDGFRβ/PI3K/AKT pathway were further confirmed in mice and transforming growth factor-β-induced hepatic stellate cells. We uncovered seven plant metabolites (chlorogenic acid, scoparone, isoliquiritigenin, glycyrrhetinic acid, formononetin, atractylenolide I, and benzoylaconitine) of YCZFD that may regulate PDGFRβ expression. Conclusion: YCZFD substantially protects against DDC-induced CLF mainly through regulating the PDGFRβ/PI3K/AKT signaling pathway.

Keywords: PDGFRβ/PI3K/AKT; Yinchenzhufu decoction; cholestasis; liver fibrosis; proteomics.

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This study is funded by the National Natural Science Foundation of China (No. 81773871) and SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program (Grant No. E2G804H).