GAS5-inhibited hepatocyte pyroptosis contributes to hepatic stellate cell inactivation via microRNA-684 and AHR

Zhichao Lang; Rongrong Zhang; Xinmiao Li; Yan Jin; Yuhang Hu; Xinyi Lin; Yunzhi Tang; Jingnan Zhang; Lei Zheng; Zhixian Yu; Jianjian Zheng

doi:10.1016/j.isci.2023.107326

GAS5-inhibited hepatocyte pyroptosis contributes to hepatic stellate cell inactivation via microRNA-684 and AHR

iScience. 2023 Jul 13;26(8):107326. doi: 10.1016/j.isci.2023.107326. eCollection 2023 Aug 18.

Authors

Zhichao Lang¹, Rongrong Zhang¹, Xinmiao Li¹, Yan Jin¹, Yuhang Hu², Xinyi Lin¹, Yunzhi Tang¹, Jingnan Zhang¹, Lei Zheng^{1

3}, Zhixian Yu⁴, Jianjian Zheng^{1

2}

Affiliations

¹ Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
² Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo 315300, China.
³ Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
⁴ Department of Urology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Abstract

Hepatocyte pyroptosis has been shown to be involved in liver damage progression. Previously, we found that growth arrest-specific 5 (GAS5) is a regulator of hepatic stellate cell (HSC) activation. However, whether GAS5 plays a role in hepatocyte pyroptosis remains unclear. In this study, reduced GAS5 was shown in CCl₄-treated mice and restoration of GAS5-inhibited liver fibrosis in vivo. Hepatocyte pyroptosis participated in the effects of GAS5-inhibited liver fibrosis, associated with reduced caspase-1, NLRP3, and IL-1β (hepatocyte pyroptosis markers). Notably, AHR expression, a suppressor of NLRP3, was enhanced by GAS5. Silencing AHR inhibited GAS5-mediated hepatocyte pyroptosis. GAS5 and AHR were targets of microRNA-684 (miR-684). In addition, the effects of GAS5 on hepatocyte pyroptosis could be inhibited by miR-684. Interestingly, GAS5-mediated hepatocyte pyroptosis contributed to HSC inactivation. In conclusion, we demonstrate that GAS5 inhibits hepatocyte pyroptosis and HSC activation, at least in part, via regulation of miR-684 and AHR.

Keywords: Biochemistry; Biological sciences; Cell biology; Molecular biology; Natural sciences.