Targeting ALOX5 ameliorates renal tubular injury in ischemia-reperfusion-induced acute kidney injury via inhibition of ferroptosis.

Ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) could be potentially lethal in clinic. We found lipoxygenases-5 (ALOX5) was upregulated in renal tubular cells in IRI-induced AKI; however, its underlying mechanism is not clear. In this study, we explore the function of ALOX in IRI-induced AKI using human renal proximal tubular epithelial cells (HK-2) and C57BL/6 mice. Alox5 knock-out mouse is constructed. Products of polyunsaturated fatty acids metabolized by ALOX5 in the kidney tissue are measured by UHPLC-HRMS/MS platform. Ferroptosis is measured upon ALOX5 intervention and Benzbromarone (BBR) intervention. The results indicate that in IRI-induced AKI, ALOX5 is up-regulated in the renal tubular epithelial cells and exacerbates the accumulation of lipid peroxides, which in turns enhances ferroptosis in the renal tubular cells and finally contributes to cell injury. BBR specifically interacts with ALOX5 and reduces the accumulation of lipid peroxide, thus alleviating the cell damage caused by IRI and improving the renal function of experimental mice. In conclusion, ALOX5 enhances the accumulation of lipid peroxide in the renal tubular cells in IRI-induced AKI and targeting ALOX5 might ameliorate renal tubular injury via inhibiting ferroptosis in this clinical setting.