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Cited by 70Liver physiology and pathologyLiver Disease Diagnosis and TreatmentLiver Diseases and Immunity

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Macrophage-Derived Cathepsin S Remodels the Extracellular Matrix to Promote Liver Fibrogenesis

Zuo, Tao, Xie, Qi, Liu, Jinfang, Yang, Jing, Shi, Jiahui, Kong, Degang, Wang, Yin, Zhang, Zhenpeng, Gao, Huixia, Zeng, Dao-Bing, Wang, Xinxin, Tao, Ping, Wei, Wei, Wang, Jun, Li, Yuan, Long, Qi, Li, Chonghui, Chang, Lei, Ning, Huimin, Li, Yanchang, Cui, Chunping, Ge, Xinlan, Wu, Jushan, Li, Guangming, Hong, Xuechuan, Yang, Xiao, Dai, Erhei, He, Fuchu, Wu, Junzhu, Ruan, Yuanyuan, Lu, Shichun, Xu, Ping·2023·Gastroenterology
DOI 10.1053/j.gastro.2023.05.039
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Abstract

Background & aims Liver fibrosis is an intrinsic wound-healing response to chronic injury and the major cause of liver-related morbidity and mortality worldwide. However, no effective diagnostic or therapeutic strategies are available, owing to its poorly characterized molecular etiology. We aimed to elucidate the mechanisms underlying liver fibrogenesis. Methods We performed a quantitative proteomic analysis of clinical fibrotic liver samples to identify dysregulated proteins. Further analyses were performed on the sera of 164 patients with liver fibrosis. Two fibrosis mouse models and several biochemical experiments were used to elucidate liver fibrogenesis. Results We identified cathepsin S (CTSS) up-regulation as a central node for extracellular matrix remodeling in the human fibrotic liver by proteomic screening. Increased serum CTSS levels efficiently predicted liver fibrosis, even at an early stage. Secreted CTSS cleaved collagen 18A1 at its C-terminus, releasing endostatin peptide, which directly bound to and activated hepatic stellate cells via integrin α5β1 signaling, whereas genetic ablation of Ctss remarkably suppressed liver fibrogenesis via endostatin reduction in vivo. Further studies identified macrophages as the main source of hepatic CTSS, and splenectomy effectively attenuated macrophage infiltration and CTSS expression in the fibrotic liver. Pharmacologic inhibition of CTSS ameliorated liver fibrosis progression in the mouse models. Conclusions CTSS functions as a novel profibrotic factor by remodeling extracellular matrix proteins and may represent a promising target for the diagnosis and treatment of liver fibrosis.

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Metadata

Authors
Zuo, T., Xie, Q., Liu, J., Yang, J., Shi, J., Kong, D., Wang, Y., Zhang, Z., Gao, H., Zeng, D.-B., Wang, X., Tao, P., Wei, W., Wang, J., Li, Y., Long, Q., Li, C., Chang, L., Ning, H., Li, Y., Cui, C., Ge, X., Wu, J., Li, G., Hong, X., Yang, X., Dai, E., He, F., Wu, J., Ruan, Y., Lu, S., & Xu, P.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Army Medical University (CN)
  • Chinese PLA General Hospital (CN)
  • Fifth Hospital of Shijiazhuang (CN)
  • Capital Medical University (CN)
  • Guangzhou University of Chinese Medicine (CN)
  • Wuhan University (CN)
  • Shanghai Medical College of Fudan University (CN)
Corresponding author
  • Wu, Junzhu
  • Ruan, Yuanyuan
  • Lu, Shichun
  • Xu, Ping
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2023-09
Volume
165
Issue
3
Pages
746-761.e16
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2023.05.039
OpenAlex
W4378840629
Cited by
70
References
6
Citations by year
2026: 32 · 2025: 22 · 2024: 12 · 2023: 4
FWCI
11.26
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • CAMS Innovation Fund for Medical Sciences
  • National Natural Science Foundation of China (32070668, 32071431, 32101190, 32141003)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords
cathepsin S, liver fibrosis, extracellular matrix remodeling, macrophages, endostatin, hepatic stellate cells, serum biomarkers, splenectomy, fibrosis diagnosis
MeSH terms
Animals, Cathepsins, Disease Models, Animal, Extracellular Matrix, Fibrosis, Humans, Liver, Liver Cirrhosis, Macrophages, Proteomics, Endostatins, Mice, Hepatic Stellate Cells

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