Intercellular communication interference through energy metabolism-related exosome secretion inhibition for liver fibrosis treatment.
10.1016/j.apsb.2025.07.008
- Author:
Mengyao ZHANG
1
;
Huaqing JING
1
;
Xinyi LIU
1
;
Valentin A MILICHKO
2
;
Yunsheng DOU
1
;
Yingzi REN
1
;
Zitong QIU
1
;
Wen LI
1
;
Weili LIU
3
;
Xinxing WANG
3
;
Nan LI
1
Author Information
1. Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin 300072, China.
2. School of Physics and Engineering, ITMO University, St. Petersburg 197101, Russia.
3. Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
- Publication Type:Journal Article
- Keywords:
Activated hepatic stellate cells;
Cu/ZIF-8;
Energy metabolism;
Exosomes;
Intercellular communication interference;
Liver fibrosis;
Paeoniflorin;
Quiescent hepatic stellate cells
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4900-4916
- CountryChina
- Language:English
-
Abstract:
As activated hepatic stellate cells (aHSCs) play a central role in fibrogenesis, they have become key target cells for anti-fibrotic treatment. Nevertheless, the therapeutic efficiency is constrained by the exosomes they secrete, which are linked to energy metabolism and continuously stimulate the activation of neighboring quiescent hepatic stellate cells (qHSCs). Herein, an intercellular communication interference strategy is designed utilizing paeoniflorin (PF) loaded and hyaluronic acid (HA) coated copper-doped ZIF-8 (PF@HA-Cu/ZIF-8, PF@HCZ) to reduce energy-related exosome secretion from aHSCs, thus preserving neighboring qHSCs in a quiescent state. Simultaneously, the released copper and zinc ions disrupt key enzymes involved in glycolysis to reduce bioenergy synthesis in aHSCs, thereby promoting the reversion of aHSCs to a quiescent state and further decreasing exosome secretion. Therefore, PF@HCZ can effectively sustain both aHSCs and qHSCs in a metabolically dormant state to ultimately alleviate liver fibrosis. The study provides an enlightening strategy for interrupting exosome-mediated intercellular communication and remodeling the energy metabolic status of HSCs with boosted antifibrogenic activity.
