〔Abstract〕 Objective To investigate the expression of Ca2+-independent phospholipase A2β(iPLA2β) in human renal tubular epithelial cells(HK-2) induced by high glucose(HG), the relationship between iPLA2β and ferroptosis and the protective mechanism of HG treated HK-2 cells. Methods The HK-2 cells were treated with 30 mmol/L glucose, the overexpression model was constructed by transfection of iPLA2β plasmid.Ferrostatin-1(Fer-1)(an inhibitor of ferroptosis)and erastin(an activator of ferroptosis) were used as controls. After 36 hours of intervention, the kit detected the levels of superoxide(SOD), malonaldehyde(MDA) and iron in HK-2 cells. DCF immunofluorescence was used to detect intracellular reactive oxygen species(ROS). The expression of ACSL4, GPX4, LPCAT3, TFR1 in HK-2 cells were measured by Western blot. Results The expression of iPLA2β downregulated in HG-induced injury of HK-2 cells. The levels of ROS and MDA in HK-2 cells increased, while the levels of GSH and SOD decreased. The expression of ACSL4, LPCAT3 and TFR1 decreased, and the expression of GPX4 increased in HK-2 cells. However, these indexes were improved after Fer-1 intervention. iPLA2β overexpression could reduce the injury of HK-2 cellsviaattenuation of KIM-1. Further research revealed that iPLA2β overexpression inhibited oxidative stress and ferroptosis in HK-2 cells injury induced by high glucose. Meanwhile, the improvement effect of iPLA2β on HG-induced HK-2 cells damage could be eliminated by erastin. Conclusion iPLA2β prevents HG-induced injury of HK-2 cellsviaregulating ferroptosis.