ABSTRACT
Cisplatin-associated acute kidney injury (AKI) is a severe clinical syndrome that significantly restricts the chemotherapeutic application of cisplatin in cancer patients. Ferroptosis, a newly characterized programmed cell death driven by the lethal accumulation of lipid peroxidation, is widely reported to be involved in the pathogenesis of cisplatin-associated AKI. Targeted inhibition of ferroptosis holds great promise for developing novel therapeutics to alleviate AKI. Unfortunately, current ferroptosis inhibitors possess low bioavailability or perform non-specific accumulation in the body, making them inefficient in alleviating cisplatin-associated AKI or inadvertently reducing the anti-tumor efficacy of cisplatin, thus not suitable for clinical application. In this study, a novel selenium nanomaterial, polyacrylic acid-coated selenium-doped carbon dots (SeCD), is rationally developed. SeCD exhibits high biocompatibility and specifically accumulates in the kidney. Administration of SeCD effectively scavenges broad-spectrum reactive oxygen species and significantly facilitates GPX4 expression by releasing selenium, resulting in strong mitigation of ferroptosis in renal tubular epithelial cells and substantial alleviation of cisplatin-associated AKI, without compromising the chemotherapeutic efficacy of cisplatin. This study highlights a novel and promising therapeutic approach for the clinical prevention of AKI in cancer patients undergoing cisplatin chemotherapy.
ABSTRACT
Ferroptosis, a newly characterized form of regulated cell death, is induced by excessive accumulation of lipid peroxidation catalyzed by intracellular bioactive iron. Increasing evidence has suggested that ferroptosis is involved in the pathogenesis of several human diseases, including acute liver injury. Targeted inhibition of ferroptosis holds great promise for the clinical treatment of these diseases. Herein, we report a simple and one-pot synthesis of ultrasmall poly(acrylic) acid coated Mn3O4 nanoparticles (PAA@Mn3O4-NPs, PMO), which perform multiple antioxidant enzyme-mimicking activities and can scavenge broad-spectrum reactive oxygen species. PMO could potently suppress ferroptosis. Mechanistically, after being absorbed mainly through macropinocytosis, PMO are largely enriched in lysosomes, where PMO detoxify ROS, inhibit ferritinophagy-mediated iron mobilization and preserve mTOR activation, which collectively confer the prominent inhibition of ferroptosis. Additionally, PMO injection potently counteracts lipid peroxidation and alleviates acetaminophen- and ischaemia/reperfusion-induced acute liver injury in mice. Collectively, our results reveal that biocompatible PMO act as potent ferroptosis inhibitors through multifaceted mechanisms, which ensures that PMO have great translational potential for the clinical treatment of ferroptosis-related acute liver injury.
