ABSTRACT: OBJECTIVE??To investigate the effects of Radix Tetrastigma Hemsleyani Flavone on pyroptosis and ferroptosis in mice with sepsis liver injury through activation of the Nrf2 signaling pathway and its molecular mechanism.METHODS Kunming mice were randomly divided into six groups: control group, model group, positive control group (dexamethasone 10 mg?kg－1), low, medium, and high dose Radix Tetrastigma Hemsleyani Flavone groups. Low, medium, and high-dose groups were pretreated with intraperitoneal injections of 60 mg?kg－1, 90 mg?kg－1, and 120 mg?kg－1. In comparison, the positive control group was pretreated with intraperitoneal injection of dexamethasone 10 mg?kg－1，for 7 days. The acute liver injury model of sepsis was established by intraperitoneal injection of LPS(10 mg?kg－1). The mice were euthanized 24 hours later, and liver and blood samples were collected. The efficacy and pharmacological mechanism of Radix Tetrastigma Hemsleyani Flavone in treating acute liver injury of sepsis were verified by gross specimen, histopathology, biochemical examination, and molecular biology examination.RESULTS ?Compared with the model group, RTHF can significantly reduce the levels of serum ALT, AST, IL-6, TNF-α, IL-1β, IL-18 and liver tissue MDA, Fe2+, and ROS in mice (P<0.01 or P<0.05 ), significantly increased SOD and GSH levels in liver tissue (P<0.01 or P<0.05), liver tissue pathology and inflammatory infiltration were improved, and liver index decreased; up-regulated the expression of Nrf2 protein and Nrf2 and HO-1 in the nucleus , SLC7A11, GPX4 protein expression (P<0.01 or P<0.05), down-regulating the expression of Cleaved-Caspase-1, Cleaved-GSDMD protein and Keap1, NLRP3, Caspase-1, Cleaved-Caspase-1, GSDMD, Cleaved -Expression of GSDMD and protein (P<0.01 or P<0.05).CONCLUSION ?Total flavonoids of Trifolium folium can reduce the release of inflammatory factors, relieve oxidative stress, inhibit iron death and NLRP3-mediated pyroptosis by activating the Nrf2 signaling pathway, and have protective effects on LPS-induced hepatic injury in mice with sepsis.