〔Abstract〕 Abstract Objective To investigate the effects of paeoniflorin (Pae) on acute kidney injury ( AKI) and mouse renal tubular epithelial cell ( mRTEC) damage induced by lansoprazole (LPZ) and cisplatin (CIS) through in vivo and in vitro experiments . Methods The C57BL/6J mice or mRTECs were divided into four groups : normal control (NC) group , NC + LPZ group , CIS group , and CIS + LPZ group . Serum creatinine (CRE) and blood urea nitro- gen (BUN) levels in mice were measured , and kidney pathology was observed with HE staining. Western blot , im- munohistochemistry , and immunofluorescence were used to detect the expression levels of kidney injury molecule-1 (KIM-1) and receptor-interacting protein kinase (RIPK) 1 , RIPK3 , and mixed lineage kinase domain-like protein (MLKL) . Subsequently , C57BL/6J mice or mRTECs were divided into six groups : NC group , NC + Pae group , CIS + LPZ (M) group , and CIS + LPZ + Pae ( M + Pae) group . Serum CRE and BUN levels in each group were measured , kidney pathology was observed with HE staining , and ultrastructural changes in the kidney were ob-served with transmission electron microscopy. The KIM-1 and necroptosis-related protein expression levels were de- tected by Western blot , immunohistochemistry , and immunofluorescence . Results Compared with the NC group , CRE and BUN levels were elevated in the CIS group , and these levels were further increased after LPZ intervention (all P < 0. 001) . Compared with the CIS group , renal tubular dilation and brush border loss were evident in the CIS + LPZ group based on HE staining of kidney tissue (P < 0. 001) . Compared with the NC group , the expres- sion levels of KIM-1 , RIPK1 , RIPK3 , and MLKL in the renal tissues of mice in the CIS group increased (all P < 0. 001) , and compared with the CIS group , The expression levels of KIM-1 , RIPK1 , RIPK3 and MLKL in the re- nal tissues of mice in the CIS + LPZ group increased (all P < 0. 001) . After Pae treatment , compared with group M , the expression levels of CRE , BUN , KIM-1 , RIPK1 , RIPK3 and MLKL in each group of mice decreased sig- nificantly and in a dose-dependent manner (all P < 0. 001) . Conclusion LPZ promotes CIS-induced AKI by en- hancing necroptosis in renal tubular epithelial cells , and Pae can improve CIS and LPZ-induced AKI by inhibiting necroptosis .