Ursolic acid alleviates Kupffer cells pyroptosis in liver fibrosis by the NOX2/NLRP3 inflammasome signaling pathway

•Pyroptosis is a novel form of programmed and proinflammatory cell death that is involved in multiple liver diseases; KC pyroptosis is increased in CCl4-induced liver fibrous mice, and UA can abrogate this effect.•KC pyroptosis promoted liver injury, inflammation and the development of liver fibrosis in mice.•Ursolic acid (UA), a natural triterpenoid, ameliorates liver fibrosis in mice via inhibiting KC pyroptosis, which may be through suppression of NOX2/NLRP3 inflammasome signaling pathway. Pyroptosis has an important role in liver inflammation and fibrosis. The role of KC pyroptosis in liver fibrosis was unclear. Ursolic acid (UA) has antifibrotic effects, but study on the effect and mechanism of UA on KC pyroptosis in liver fibrosis has not been reported. Therefore, we induced KC pyroptosis using Lipopolysaccharide (LPS) and nigericin (Nig) in vitro. C57BL/6J mice were intraperitoneally injected with carbon tetrachloride (CCl4) to establish a liver fibrosis model. We demonstrated that UA attenuated CCl4-induced liver fibrosis, liver damage, and KC pyroptosis of liver tissue. Moreover, KCs were treated with UA and small interfering RNA of NOX2, which showed that inhibiting the NOX2/NLRP3 inflammasome signaling pathway attenuated KC pyroptosis and UA abrogated this effect via suppressing this pathway in vitro. Furthermore, mice were treated with UA, GSK2795039 (a specific inhibitor of NOX2) or MCC950 (a specific inhibitor of NLRP3). Compared with inhibiting NOX2 alone, inhibiting NOX2 in the presence of UA did not markedly ameliorate KC pyroptosis of liver tissue in CCl4-induced liver fibrosis. In addition, when NLRP3 was silenced or inhibited, the result was similar to that of knocking down NOX2 in vivo and in vitro. These results indicate that UA attenuates liver fibrosis in mice via inhibiting KC pyroptosis, which may be through the suppression of NOX2/NLRP3 inflammasome signaling pathway. It may be a new target for treating liver fibrosis and provide a new theoretical basis for the use of UA to treat liver fibrosis.