Environmental cadmium exposure perturbs systemic iron homeostasis via hemolysis and inflammation, leading to hepatic ferroptosis in common carp (Cyprinus carpio L.).

Cadmium (Cd) pollution is considered a pressing challenge to eco-environment and public health worldwide. Although it has been well-documented that Cd exhibits various adverse effects on aquatic animals, it is still largely unknown whether and how Cd at environmentally relevant concentrations affects iron metabolism. Here, we studied the effects of environmental Cd exposure (5 and 50 µg/L) on iron homeostasis and possible mechanisms in common carp. The data revealed that Cd elevated serum iron, transferrin saturation and iron deposition in livers and spleens, leading to the disruption of systemic iron homeostasis. Mechanistic investigations substantiated that Cd drove hemolysis by compromising the osmotic fragility and inducing defective morphology of erythrocytes. Cd concurrently exacerbated hepatic inflammatory responses, resulting in the activation of IL6-Stat3 signaling and subsequent hepcidin transcription. Notably, Cd elicited ferroptosis through increased iron burden and oxidative stress in livers. Taken together, our findings provide evidence and mechanistic insight that environmental Cd exposure could undermine iron homeostasis via erythrotoxicity and hepatotoxicity. Further investigation and ecological risk assessment of Cd and other pollutants on metabolism-related effects is warranted, especially under the realistic exposure scenarios.

In Vitro Ferroptotic and Antitumor Effect of Free or Liposome-Encapsulated Artesunate in Papillary Thyroid Cancer Cells.

Papillary thyroid cancer (PTC) is generally treated as an indolent and curable cancer. However, the unavailability of surgery and ineffective radiotherapy persists in PTCs, resulting in poor outcomes and low survival rates. Thus, new chemotherapeutic strategies for PTCs are urgently needed. Resistance to ferroptosis remarkably contributes to cancer occurrence and progression. Artesunate (ART) has been repurposed as an anticancer drug, as it induces cell death in numerous cancers. However, whether ART induces ferroptosis in PTC cells and, consequently, facilitates PTC therapy remains elusive. Furthermore, overcoming the pharmacological limitations of ART is a key requirement to support its clinical application. Herein, we reanalyzed the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression database (GTEx) to characterize the occurrence of resistance to ferroptosis in thyroid cancer. In vitro results showed that ART induced ferroptosis in PTC cells by increasing the cellular iron content. The encapsulation of ART by liposomes did not alter the efficiency in inducing ferroptosis and inhibiting the invasion and migration of PTC cells compared with direct ART application. Thus, PTC resistance to ferroptosis can be overcome by ART and liposome-encapsulated ART.

Implication of ferroptosis in hepatic toxicity upon single or combined exposure to polystyrene microplastics and cadmium.

Microplastics (MPs) are a newly emerging type of pollutants. To date, MPs have been found in the atmosphere, soil, water, and even in human samples, posing a non-negligible threat to humans. Furthermore, multiple heavy metals have been found to co-exist with MPs or be absorbed by MPs. This leads to a widespread concern about their combined toxicity, which is currently elusive. Herein, we investigated the single or combined toxic effects of polystyrene MPs (PS-MPs) and cadmium chloride (CdCl2) on the liver and hepatocytes. After co-incubation, cadmium (Cd) can be absorbed by PS-MPs, resulting in physiochemical alterations of PS-MPs. In vivo and in vitro experiments revealed that PS-MPs solely or together with CdCl2 induced ferroptosis in hepatocytes, a newly defined programmed cell death characterized by lipid oxidation and iron accumulation. PS-MPs exerted more ferroptotic effect on hepatocytes than CdCl2, and combined exposure to PS-MPs and CdCl2 enhanced their ferroptotic effect, mainly by stimulating reactive oxygen species (ROS) production and inhibiting antioxidant activity. Upon single or combined exposure to PS-MPs and CdCl2, the induction of ferroptosis in hepatocytes can be inhibited by N-acetyl-cysteine (NAC, an ROS scavenger), deferoxamine (DFO, an iron chelator), and particularly ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). Fer-1 efficiently rescued the cell viability of hepatocytes upon exposure to PS-MPs and CdCl2 through enhancing the antioxidant system via upregulating GPX4 and SLC7A11. These findings would contribute to an in-depth understanding of the single and combined toxicity of microplastics and cadmium.

Implications of ferroptosis in silver nanoparticle-induced cytotoxicity of macrophages.

Metal nanoparticles (NPs) are widely used in daily life and commercial activities owing to their unique physicochemical properties. Consequently, there is an increasing risk of daily and occupational exposure to metal NPs, which raises concerns regarding their health hazards. Programmed cell deaths (PCDs) have been clarified to be involved in metal NP-induced cytotoxicity, including apoptosis, autophagy, and pyroptosis. However, whether and how ferroptosis, a newly recognized PCD, contributes to metal NP-induced cell death remain unclear. In this study, we investigated the ferroptotic effects of two representative metal NPs, silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs), on macrophages in vitro. Our results revealed that AgNPs, rather than AuNPs, induced non-apoptotic PCD, accompanied by lipid peroxidation and iron homeostasis disorders, which are two hallmarks of ferroptosis, in macrophages. Treatment with a ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine) reversed AgNP-induced PCD, corroborating the induction of ferroptosis upon exposure to AgNPs. Moreover, our results revealed that smaller AgNPs elicited greater ferroptotic effects on macrophages than larger ones. Importantly, ferroptosis in AgNP-treated macrophages was mainly triggered by AgNPs per se rather than by Ag ions. Overall, our study highlights the ferroptotic effects elicited by AgNPs in macrophages, which will promote the understanding of their cytotoxic effects and facilitate the safer design of metal nanoproducts.

Antimony exposure promotes bladder tumor cell growth by inhibiting PINK1-Parkin-mediated mitophagy.

Antimony is one of the heavier pnictogens and is widely found in human food chains, water sources, and as an air pollutant. Recent years have seen steadily increasing concentrations of antimony in the ecological environment; critically, several studies have indicated that antimony might pose a tumorigenic risk factor in several cancers. Therefore, antimony toxicity has attracted increasing research attention, with the molecular mechanisms underlying suspected antimony-mediated tumor transformation of greatest interest. Our results showed that the serum concentration of antimony was higher in bladder tumor patients relative to levels in non-tumor patients. Moreover, that such high antimony serum concentration were closely associated with poorer outcome in bladder tumor patients. Additionally, we demonstrated that the presence of antimony promoted both in vitro and in vivo bladder tumor cell growth. Our results also indicated that low-dose antimony resulted in significantly decreased mitochondrial membrane potential, mitochondrial respiratory enzyme complex I/II/III/IV activity, ATP/ADP ratio, and ATP concentration relative to the control group. These findings suggested that antimony caused mitochondrial damage. Finally, we found that low-dose antimony(0.8uM) inhibited mitophagy by deregulating expression of PINK1, Parkin, and p(ser65)-Parkin, and activation of PINK1-Parkin pathway by CCCP could inhibit antimony-induced tumor cell growth. Collectively, this inhibited the proliferation of bladder tumor cells. Overall, our study suggested that antimony promoted bladder tumor cell growth by inhibiting PINK1-Parkin-mediated mitophagy. These findings highlight the therapeutic potential in targeting molecules within this antimony induced-PINK1/Parkin signaling pathway and may offer a new approach for the treatment of bladder cancer.