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Targeting Ferroptosis by Natural Compounds in Nephrotoxicity: A Review
Fatemeh Darvishzadeh Mahani1, Azhdar Heydari2, Reihaneh Sadeghian3
1Physiology Research Center, Institute for Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
Abstract:
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.
Insights
Natural compounds protect kidneys from toxic damage by reducing ferroptosis, a cell death pathway involving iron and oxidative stress. These compounds modulate key pathways to prevent kidney injury from nephrotoxic agents.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Nephrotoxicity, kidney damage from toxins, can lead to acute or chronic kidney injury.
- Ferroptosis, an iron-dependent cell death, is implicated in nephrotoxicity pathogenesis due to lipid peroxide accumulation.
- Natural compounds like curcumin, quercetin, and baicalein show potential in mitigating kidney damage.
Purpose of the Study:
- To review the protective effects of natural compounds against nephrotoxicity.
- To elucidate the mechanisms by which natural compounds inhibit ferroptosis in kidney injury models.
- To highlight the targeted pathway modulation by natural compounds in different nephrotoxicity contexts.
Main Methods:
- Literature review of studies investigating natural compounds and nephrotoxicity.
- Analysis of molecular pathways involved in ferroptosis and their modulation by natural compounds.
- Comparison of ferroptosis mechanisms across different nephrotoxic agents (e.g., cisplatin, adriamycin).
Main Results:
- Natural compounds enhance protective pathways (GPX4, Nrf2/GPX4, SIRT1/p53) against ferroptosis.
- These compounds suppress detrimental pathways (Hippo, HIF-2α/DUOX1/GPX4, ERK1/2, ALOX12, ferritinophagy).
- Ferroptosis mechanisms vary with nephrotoxic agents, requiring targeted natural compound intervention.
Conclusions:
- Natural compounds offer a promising therapeutic strategy for kidney protection.
- Mitigation of ferroptosis by natural compounds is a key mechanism in preventing nephrotoxicity.
- Targeted application of natural compounds based on specific ferroptotic pathways shows potential for treating kidney injury.
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