Acute kidney injury (AKI) is a heterogeneous clinical complication with no existing definite or particular therapies. Therefore, molecular mechanisms and approaches for treating acute kidney injury are in urgent need. Herein, we demonstrated that dexrazoxane (DXZ), a U.S. Food and Drug Administration (FDA)-approved cardioprotective drug, can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically. This effect is characterized by decreasing lipid peroxidation, shown by the biomarker of oxidative stress 4-hydroxynonenal (HNE) and prostaglandinendoperoxide synthase 2 (Ptgs2), while reversing the downregulation of glutathione peroxidase 4 (GPX4) and ferritin 1 (FTH-1). Mechanistically, the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressing α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). Furthermore, the conjugation of dexrazoxane and polysialic acid (DXZ-PSA) is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney, especially retention and targeting in the renal tubules. This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZ-PSA with the enhanced renal distribution.

Ferroptosis plays a critical pathophysiological role in several types of acute kidney injury (AKI). The development of nanomaterials targeting iron metabolism and ferroptosis is a promising approach for AKI treatment. Herein, we synthesized gallic acid-gallium polyvinyl pyrrolidone nanoparticles (GGP NPs) as a potential iron-scavenging agent because of their nearly ionic radius and chemical similarity with iron. The results indicated that GGP NPs accumulated in tubular epithelial cells and showed good biocompatibility. GGP NPs significantly inhibited cisplatin (CP)-induced ferroptosis in HK-2 cells by reducing the accumulation of intracellular free iron and mitochondrial dysfunction, and suppressing the perturbations of ferroptosis processes, including lipid peroxidation, nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) levels, glutathione peroxidase 4 (GPX4) activity, and ferritinophagy. An in vivo study demonstrated that treatment with GGP NPs significantly ameliorated the renal tubular injury and mitochondrial damage induced by CP treatment or ischemia-reperfusion injury. Our study suggests that GGP NPs may be an effective and promising candidate for AKI treatment and enable potential clinical translation.

Acute kidney injury (AKI), has become the focus of increasing attention due to its high risk of death. The early diagnosis and treatment of AKI significantly reduce the risk of renal tissue damage and kidney dysfunction. However, the efficient early diagnosis and treatment approach for AKI remains a challenge. AKI screening via precise nanomaterial theranostics is a new alternative approach. This study summarizes the recent advances in functional nanomaterials in the early detection and treatment of AKI. The challenges and problems in the use of nanomaterials for AKI in clinical applications are also discussed. It is anticipated that highlighting these new advances will lay the foundation for further translational research on the promising application of nanomaterials for AKI.