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Hepatic HRC induces hepatocyte pyroptosis and HSCs activation via NLRP3/caspase-1 pathway

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Abstract

The histidine-rich calcium-binding protein (HRC) is a regulator of Ca2 + homeostasis and it plays a significant role in liver fibrosis. Pyroptosis, a specific inflammatory cell death, can lead to hepatic stellate cells (HSCs) activation and liver fibrosis. However, the role of HRC in pyroptosis has not been explored. In this study, we demonstrated that HRC, mainly located in the hepatocyte, was over expressed in fibrotic liver tissues. We further found that enforced expression of HRC in hepatocytes induced pyroptosis and HMGB1 release, and subsequently led to HSCs activation by NLRP3/caspase-1 pathway. In addition, the proliferation and migration of HSCs were also enhanced by HRC overexpression in hepatocytes. Furthermore, NLRP3 inhibitor MCC950 and caspase-1 inhibitor VX-765 alleviated hepatic HRC-mediated hepatocytes pyroptosis and HSCs activation. This study demonstrated that hepatic HRC promoted HSCs activation by inducing hepatocyte pyroptosis, which suggests that HRC may be a promising therapeutic target to prevent liver fibrosis.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

HRC:

Histidine-rich calcium-binding protein

α-SMA:

α-Smooth actin

CCl4:

Carbon tetrachloride

ALT:

Aminotransferase

AST:

Aspartic aminotransferase

LDH:

Lactate dehydrogenase

H&E:

Hematoxylin-eosin

IHC:

Immunohistochemistry

GSDMD:

Gasdermin D

GSDMD-N:

N-terminal fragment of GSDMD

NLRP3:

Nod-like receptor protein 3

IL-1β:

Interleukin-1β

IL-18:

Interleukin-18

HMGB1:

High mobility group box 1

LPS:

Lipopolysaccharide

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Funding

This study was funded by the National Natural Science Foundation of China (Nos. 81800547, 81672392).

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Author notes

  1. Jingwen Wu and Mingyu Zhang contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China

    Jingwen Wu, Mingyu Zhang, Suhong Xia, Ping Han, Kai Zhao, Kaixin Peng, Wangdong Zhou, Dean Tian, Jiazhi Liao & Jingmei Liu

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  1. Jingwen Wu
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Contributions

JM. Liu and DA. Tian designed the study. JW. Wu, SH, Xia and WD. Zhou performed the experiments. P. Han, K. Zhao and MY. Zhang analyzed the data. JW. Wu, JM. Liu and KXP prepared the manuscript. JM. Liu and JZ. Liao provide financial support. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Jiazhi Liao or Jingmei Liu.

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Ethics approval

The animal study was reviewed and approved by The Institution Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. This study was performed according to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Tongji Hospital, Huazhong University of Science and Technology following the ethical and institutional guidelines.

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The authors declare no competing interests.

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Key message

•   Histidine-rich calcium-binding protein (HRC) is overexpressed in fibrotic liver tissues.

•   HRC triggers cell pyroptosis and HMGB1 release.

•   HRC induces HSCs activation, proliferation and migration.

•   HRC mediates hepatocyte pyroptosis and HSCs activation via NLRP3/caspase-1 pathway.

•   HRC may be a promising therapeutic target to prevent liver fibrosis.

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Wu, J., Zhang, M., Xia, S. et al. Hepatic HRC induces hepatocyte pyroptosis and HSCs activation via NLRP3/caspase-1 pathway. J Mol Med 100, 1787–1799 (2022). https://doi.org/10.1007/s00109-022-02270-8

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