Objective To investigate the protective effect of hederagenin (HDG) on cisplatin (Cis)-induced acute kidney injury (AKI) in mice and its potential mechanism. Methods 24 male C57BL / 6J mice were randomly divided into a control group, AKI model group, HDG low-dose group, and HDG high-dose group, with six mice in each group. AKI model was established by intraperitoneal injection of 20 mg / kg cisplatin(Cis). The HDG low-dose and HDG high-dose groups were given 20, 40 mg / kg HDG by intragastric administration, respectively, and samples were collected 3 days later. The kidneys of the mice were collected for hematoxylin-eosin (HE) and periodic-acidschiff (PAS) staining to evaluate the kidney pathology, and serum was collected to detect changes in serum creatinine(Scr) and blood urea nitrogen ( BUN). The expression of p-P65, P65, IL-6, TNF-α, IL-1β, and other inflammatory-related proteins was detected by Western Blot. A TCMK1 ( renal tubular epithelial cell) inflammatorycell 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 group were set up. In the Axin2-overexpression group, the expression of p-P65, P65, IL-6, TNF-α, IL-1β, Axin2, and AREG was detected among total cell proteins. Results Compared with the control group, AKI model mice exhibited significantly elevated serum creatinine and blood urea nitrogen levels ( P<0. 05), accompanied by pathological alterations including vacuolar degeneration of renal tubules, inflammatory cell infiltration, and glycogen deposition, and the expression of inflammation-related proteins (p-P65, TNF-α, IL-6, IL-1β) and Axin2 was markedly upregulated in AKI mice (P<0. 05). HDG treatment induced a dose-dependent reduction in serum creatinine and blood urea nitrogen levels (highdose > low-dose, P<0. 05), alleviated renal histopathological damage, and concurrently suppressed the expressionof these inflammatory mediators and Axin2 (P<0. 05). HDG was confirmed that dose-dependently inhibited Cisinduced upregulation of Axin2, and inflammatory cytokines in vitro experiments. Transcriptome sequencing revealed that Axin2 overexpression significantly increased amphiregulin (AREG) expression (P<0. 05). Mechanistically,HDG reduced p-P65 phosphorylation by suppressing the Axin2 / AREG axis (P<0. 05), while Axin2 overexpression abolished the protective effects of HDG against Cis-induced renal tubular cell injury. Conclusions HDG protects against renal injury in AKI mice by reducing inflammation through the inhibition of Axin2 / AREG axis activation.