Targeting Labile Iron-Mediated Ferroptosis on Renal Proximal Tubular Epithelial Cells Provides a Potential Therapeutic Strategy for Rhabdomyolysis-Induced Acute Kidney Injury

Abstract Acute kidney injury (AKI) is a global health problem and occurring in a variety of clinical settings. Despite some advances in supportive clinical care, no medicinal intervention has been demonstrated to reliably prevent AKI so far. Thus, it is highly demand to investigate the involved pathophysiology and mechanisms, as well as discover therapeutics on the basis. In this work, an upregulated mRNA level of ferroptosis biomarkers ( Ptgs2 and Acsl4 ), and an elevated renal iron and malondialdehyde (MDA) level were observed in the early stage of murine rhabdomyolysis induced-AKI (RM-AKI), which support a pathogenic role of labile iron-mediated ferroptosis and provide a chance of utilizing iron chelation for RM-AKI preventions. Given that the existing small molecule-based iron chelators did not show promising preventions against RM-AKI, we further designed and synthesized a new hydroxypyridinone-based iron chelators for potently inhibiting labile iron-mediated ferroptosis. And a lead AKI-02 was identified with remarkable protection of renal proximal tubular epithelial cells from ferroptosis and excellent iron chelation ability. Moreover, administration of AKI-02 led to a recovery of renal function, which was substantiated by the decreased BUN and creatinine, as well as reduced labile iron level and improved histopathology. Thus, our studies highlighted the targeting labile iron-mediated ferroptosis as a therapeutic benefit against RM-AKI.