1,3‐Dichloro‐2‐propanol induced ferroptosis through Nrf2/ARE signaling pathway in hepatocytes

Abstract

1,3-Dichloro-2-propanol (1,3-DCP) is a representative chloropropane environmental contaminant with multiple toxicities. Ferroptosis is a novel iron-dependent form of regulated cell death that is closely associated with the accumulation of lipid peroxides, Fe 2+ and reactive oxygen species (ROS). In this study, we found that 1,3-DCP could induce mouse liver injury via ferroptosis. Administrating of C57BL/6J mice with 12.5, 25, and 50 mg/kg 1,3-DCP for 4 weeks via oral gavage, the data showed that 1,3-DCP exposure led to the pathological changes in mouse livers, remarkably induced accumulation of malondialdehyde (MDA) and Iron, reduction of glutathione (GSH), and changed in the expression of ferroptosis marker proteins glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase-4 (ACSL4). Then, we also proved the results with HepG2 cells in vitro. The data showed that treatment 1,3-DCP significantly triggered the ferroptosis in vitro. Furthermore, we found that the ferroptosisrelated signal pathways were significantly activated in mice livers and HepG2 cells in response to 1,3-DCP exposure. The data showed that 1,3-DCP induced ferroptosis by inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into nuclear and thereby suppressing the expression of its downstream target proteins including GPX4, ferritin heavy chain (FTH), ferroportin (FPN), cystine/glutamate transporter xCT (SLC7A11), and heme oxygenase 1 (HO-1). Taken together, our findings confirmed that 1,3-DCP induced ferroptosis via the Nrf2/ARE signaling pathway in hepatocytes. Our works provide new toxicity mechanisms of 1,3-DCP with ferroptosis on hepatocytes injury.

CircRNA circSTIL inhibits ferroptosis in colorectal cancer via miR‐431/SLC7A11 axis

“…CRC is one of the common malignancies in China, and results in high incidence and mortality 25 . Ferroptosis, a programmed cell death characterized by iron metabolism and ROS accumulation, was reported to be involved in the pathogenesis of many injury models, such as acute lung injury (ALI), 26 liver injury, 27 and neuronal injury 28 . In recent years, ferroptosis induction has been regarded as a promising therapeutic approach for various cancers, such as acute myeloid leukemia, 29 nasopharyngeal carcinoma, 30 gastric cancer, 31 and breast cancer 32 .…”

Ferroptosis Induced by Pollutants: An Emerging Mechanism in Environmental Toxicology

“…Guan et al investigated the hepatotoxicity of 1,3-DCP and revealed its ability to induce ferroptosis in mouse liver cells. 79 Exposure to 1,3-DCP was shown to induce pathological changes, including the accumulation of iron and malondialdehyde (MDA), reduced GSH levels, and altered expression of ACSL4 and GPX4. Zhang et al investigated the effects of acrolein, a food and environmental pollutant associated with diabetes.…”

“…Recently, emerging evidence has suggested that ferroptosis could play a role in VOC-induced toxicity. Guan et al investigated the hepatotoxicity of 1,3-DCP and revealed its ability to induce ferroptosis in mouse liver cells . Exposure to 1,3-DCP was shown to induce pathological changes, including the accumulation of iron and malondialdehyde (MDA), reduced GSH levels, and altered expression of ACSL4 and GPX4.…”

Investigations into ferroptosis in methylmercury‐induced acute kidney injury in mice

“…Solute carrier family 7 member 11 (SLC7A11) is a crucial subunit of the amino acid reverse transport system x c − , 28,29 and its silencing ultimately leads to GSH degradation and ferroptosis 20,21 . Furthermore, ferroptosis has been linked to increased levels of the two lipid peroxidation products malondialdehyde (MDA) 30 and 4‐hydroxynonenal (4HNE) 31 . Another pathway correlated with ferroptosis is the amplification of the esterification of arachidonoyl and adenosyl into PE by Acyl‐CoA synthetase long‐chain family member 4 (ACSL4) 32–34 .…”