Mechanistic insights into cadmium-induced nephrotoxicity: NRF2-Driven HO-1 activation promotes ferroptosis via iron overload and oxidative stress in vitro

May 1, 2025Free radical biology & medicine

How Cadmium Causes Kidney Cell Damage: Protective NRF2-HO-1 Activity May Trigger Iron Overload and Cell Death from Oxidative Stress in Lab Cells

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Abstract

Cadmium exposure induces ferroptosis in kidney cells and tissues.

Ferroptosis is associated with iron overload, lipid peroxidation, and mitochondrial dysfunction following cadmium exposure.
Transcriptomic analysis shows significant upregulation of heme oxygenase-1 (HO-1) after cadmium exposure.
Cadmium triggers the movement of a specific protein, NRF2, into the cell nucleus, activating HO-1 transcription.
Overactive HO-1 leads to the breakdown of heme and release of free iron, contributing to ferroptosis.
Inhibition of HO-1 or genetic knockout reduces ferroptosis in kidney cells exposed to cadmium.
In vivo studies confirm that NRF2/HO-1 pathways are involved in kidney damage caused by cadmium.

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Cadmium (Cd), a pervasive environmental toxicant, poses significant threats to human and animal health through multi-organ toxicity. While ferroptosis has been implicated in Cd-induced pathologies, the molecular mechanisms underlying Cd-mediated nephrotoxicity remain poorly understood. This study elucidates the ferroptosis pathway in CdCl-exposed PK-15 cells and murine kidney, characterized by iron overload, lipid peroxidation, and mitochondrial dysfunction, which were ameliorated by ferroptosis inhibitor ferrostatin-1. Transcriptomic analysis revealed substantial upregulation of heme oxygenase-1 (HO-1) following CdClexposure. Mechanistically, CdCltriggered nuclear translocation of nuclear factor erythroid 2-related factor-2 (NRF2), subsequently activating HO-1 transcription. Over-activated HO-1 catalyzes the decomposition of heme and releases free iron, accompanied with the degradation of ferritin heavy chain 1 (FTH1) induced by CdClexposure, which leads to intracellular iron overload and excessive lipid peroxides production through Fenton reaction, resulting in ferroptosis ultimately. In vivo validation confirmed NRF2/HO-1-mediated ferroptosis in CdCl-induced murine nephrotoxicity. Both pre-treatment with HO-1 competitive inhibitor Zinc protoporphyrin IX (ZnPP) and knockout of HO-1 gene remarkably alleviated PK-15 cells against ferroptosis induced by CdCltreatment. Our findings demonstrate that Cd exposure initiates NRF2-mediated HO-1 overexpression, driving iron-dependent lipid peroxidation and subsequent ferroptosis. This mechanistic insight provides potential therapeutic targets for mitigating Cd-induced renal damage, advancing our understanding of heavy metal toxicity and its cellular consequences. 2 2 2 2 2 2

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Mechanistic insights into cadmium-induced nephrotoxicity: NRF2-Driven HO-1 activation promotes ferroptosis via iron overload and oxidative stress in vitro

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