Targeting Ferroptosis by Natural Compounds in Nephrotoxicity: A Review.

Nephrotoxicity refers to the damage caused to the kidneys by drugs and toxic substances, leading to acute and chronic kidney injury. Ferroptosis is a type of iron-driven cell death where oxidative stress causes lipid peroxide accumulation in cells, which is critical in the nephrotoxicity pathogenesis. Several studies have investigated the protective effects of natural compounds against nephrotoxicity, including curcumin, quercetin, and baicalein. This review highlights that natural compounds reduce ferroptosis in nephrotoxicity by enhancing protective pathways such as GPX4, Nrf2/GPX4, and SIRT1/p53, while suppressing harmful pathways including Hippo, HIF-2α/DUOX1/GPX4, ERK1/2, ALOX12, and ferritinophagy. Notably, ferroptosis mechanisms and pathway involvement may differ depending on the nephrotoxic agent; for example, cisplatin-induced injury prominently involves NCOA4-mediated ferritinophagy and iron dyshomeostasis, while adriamycin may activate distinct oxidative stress and lipid peroxidation pathways. Thus, natural compounds may target specific ferroptotic pathways depending on the nephrotoxicity model. Overall, natural compounds offer promising therapeutic strategies for kidney protection against nephrotoxic agents by mitigating ferroptosis.