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.