Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis

Background and Purpose Liver fibrosis is a wound‐healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver...

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Published in:Liver international 2024-08, Vol.44 (8), p.1937-1951
Main Authors: Hou, Li‐Shuang, Zhai, Xiao‐Pei, Zhang, Yao‐Wen, Xing, Jie‐Hua, Li, Chen, Zhou, Si‐Yuan, Zhu, Xiao‐Hong, Zhang, Bang‐Le
Format: Article
Language:English
Subjects:
Autophagy
autophagy inhibition
Biocompatibility
Drug delivery
Drug development
Extracellular matrix
Fibrosis
Health services
hepatic stellate cell
Hepatocytes
Homogeneity
Hydroxychloroquine
In vivo methods and tests
Liver
Liver cirrhosis
Liver diseases
liver fibrosis
Nanoparticles
Stellate cells
targeted therapy
Thioacetamide
Toxic diseases
Toxicity
Vitamin A
Wound healing
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Summary:Background and Purpose Liver fibrosis is a wound‐healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. Methods The delivery system of HCQ@retinol‐liposome nanoparticles (HCQ@ROL‐LNPs) targeting aHSC was constructed by the film dispersion and pH‐gradient method. TGF‐β‐induced HSC activation and thioacetamide (TAA)‐induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL‐LNPs in liver fibrosis were studied subsequently in vitro and in vivo. Results HCQ@ROL‐LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL‐LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. Conclusion Construction of HCQ@ROL‐LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.
ISSN:1478-3223
1478-3231
1478-3231
DOI:10.1111/liv.15915