To investigate the regulatory effects of Huoxue Digui Decoction(HXDGT) on high glucose-induced ferroptosis in podocytes and to elucidate its therapeutic mechanism in diabetic kidney disease(DKD).Methods:MPC-5 podocytes were cultured in vitro and divided into normal，DKD，HXDGT，Nrf2 activator(Sulforaphane)，and nuclear factor erythroid 2-related factor 2(Nrf2) inhibitor(ML385) groups.Immunofluorescence staining was used to detect the expression and localization of podocin，nephrin，glutathione peroxidase 4(GPX4)，acyl-CoA synthetase long-chain family member 4(ACSL4)，Nrf2，and ferroportin 1(FPN1).Western blot was employed to assess the protein expression of GPX4，ACSL4，Nrf2，and FPN1.Prussian blue staining was performed to evaluate intracellular iron accumulation in podocytes.Results:Compared with the normal group，the DKD group exhibited reduced fluorescence intensities of podocin，nephrin，GPX4，Nrf2，and FPN1，and increased fluorescence intensity of ACSL4.Protein expression levels of GPX4，Nrf2，and FPN1 were significantly downregulated(P<0.01)，while ACSL4 was significantly upregulated(P<0.01)，accompanied by enhanced Prussian blue staining.Compared with the DKD group，both the HXDGT and Sulforaphane groups showed enhanced fluorescence intensities of podocin，nephrin，GPX4，Nrf2，and FPN1，and reduced ACSL4 fluorescence.Additionally，GPX4 expression was significantly upregulated(P<0.01)，Nrf2 expression was upregulated(P<0.05)，and FPN1 expression was elevated(P<0.01，P<0.05)，with reduced Prussian blue staining.Conclusion:HXDGT may exert its protective effects on podocytes and therapeutic action against DKD by upregulating Nrf2 protein expression，promoting FPN1 protein expression，alleviating iron accumulation，and thereby inhibiting ferroptosis.