Thorium(IV) triggers ferroptosis through disrupting iron homeostasis and heme metabolism in the liver following oral ingestion

Thorium is a byproduct of the rare earth mining industry and can be utilized as fuel for the next-generation nuclear power facilities, which may pose health risks to the population. Although published literature has shown that the toxicity of thorium possibly originates from its interactions with iron/heme-containing proteins, the underlying mechanisms are still largely unclear. Since the liver plays an irreplaceable role in iron and heme metabolism in the body, it is essential to investigate how thorium affects iron and heme homeostasis in hepatocytes. In this study, we first assessed the liver injury in mice exposed to tetravalent thorium (Th(IV)) in the form of thorium nitrite via the oral route. After a two-week oral exposure, thorium accumulation and iron overload were observed in the liver, which are both closely associated with lipid peroxidation and cell death. Transcriptomics analysis revealed that ferroptosis, which has not previously been documented in cells for actinides, is the main mechanism of programmed cell death induced by Th(IV). Further mechanistic studies suggested that Th(IV) could activate the ferroptotic pathway through disrupting iron homeostasis and generating lipid peroxides. More significantly, the disorder of heme metabolism, which is crucial for maintaining intracellular iron and redox homeostasis, was found to contribute to ferroptosis in hepatocytes exposed to Th(IV). Our findings may shed light on a key mechanism of hepatoxicity in response to Th(IV) stress and provide in-depth understanding of the health risk of thorium.