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

Author:

Hou Li‐Shuang1,Zhai Xiao‐Pei1,Zhang Yao‐Wen1,Xing Jie‐Hua1,Li Chen1,Zhou Si‐Yuan12,Zhu Xiao‐Hong3,Zhang Bang‐Le12ORCID

Affiliation:

1. Department of Pharmaceutics, School of Pharmacy Fourth Military Medical University Xi'an China

2. Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine Fourth Military Medical University Xi'an China

3. Department of Drug Quality Management Shannxi Institute for Food and Drug Control Xi'an China

Abstract

AbstractBackground and PurposeLiver 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.MethodsThe 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.ResultsHCQ@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.ConclusionConstruction 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.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Shanxi Province

Publisher

Wiley

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