Objective To investigate the preventive effect of Hederageninhederagenin (HDG) on cisplatin (Cis)-induced acute kidney injury (AKI) in mice and its potential mechanism. Methods 24 male C57BL/6 mice were randomly divided into a control group, AKI model group, HDG low-dose HDG group, and HDG high-dose HDG group, with 6 six mice in each group. Mice A mouse acute kidney injury (AKI) model was established by intraperitoneal injection of 20mg20 mg/kg cisplatinCis. The low-dose group and high-dose groups were given 20 mg/kg and , 40 mg/kg HDG by intragastric administration, respectively, and samples were collected 3 days later. The kidneykidneys of the mice waswere collected for hematoxylin-eosin (HE) and periodic-acid-schiff (PAS) staining to evaluate the kidney pathology, theand serum was collected to detect the changes ofin creatinine (Scr) and urea nitrogen (BUN), and the). The expression of p-P65, P65, IL-6, TNF-α, IL-1β, and other inflammatory -related proteins was detected by WesternWestern Blot. A TCMK1 (renal tubular epithelial cell) inflammatory cell model was established by Cis (200 ng/ml) stimulation in vitro. Blank group, Cis model group, HDG low-dose group, HDG high-dose group, Axin2 overexpression group, HDG+Axin2 overexpression groupA Blank group, Cis model group, HDG low-dose group (10 μμg/ml)), and HDG high-dose group (30 μμg/ml) were set up. In the Axin2 -overexpression group (Cis+HDG+Axin2-OE), the expression changes of p-P65, P65, IL-6, TNF-α, IL-1β, Axin2, and AREG werewas detected after receivingamong total cell proteins. Results Compared withto the control group, the model group mice’s Scr and BUN levels of mice in model group were significantly increased in AKI model group mice,; their renal tissue pathological damage was more serious, the expressions ; their expression of inflammation-related proteins p-P65, IL-6, TNF-α, and IL-1β were significantly increased,; and the expressionstheir expression of Axin2 and AREG werewas increased (P < 0.05). Compared withto the model group, Scr and BUN in the low- and high -dose HDG group groups’ Scr and BUN were not reduced to the same extent, ; their kidney tissue pathological damage of kidney tissue was significantly alleviated,; and their protein expression levels of p-P65, IL-6, TNF-α, IL-1β, Axin2, and AREG were significantly decreased (P < 0.05). Compared to HDG group, Axin2 overexpression group weakened the The protective effect of HDG on AKI was weaker in the Axin2-overexpression group than in the HDG groups (P < 0.05). Conclusion HDG may prevent kidney injury and inflammation in AKI mice by inhibiting the Axin2/AREG axis.