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Arsenic exposure has been closely linked to hepatic insulin resistance (IR) and ferroptosis with the mechanism elusive. Peroxisome proliferator γ-activated receptor coactivator 1-α (PGC-1α) is essential for glucose metabolism as well as for the production of reactive oxygen species (ROS). However, it was unclear whether there is a regulatory connection between PGC-1α and ferroptosis. Besides, the definitive mechanism of arsenic-induced hepatic IR progression remains to be determined. Here, we found that hepatic insulin sensitivity impaired by sodium arsenite (NaAsO 2 ) could be reversed by inhibiting ferroptosis. Mechanistically, we found that PGC-1α suppression inhibited the protein expression of glutathione s-transferase kappa 1 (GSTK1) via nuclear respiratory factor 1 (NRF1), thereby increasing ROS accumulation and promoting ferroptosis. Furthermore, we showed that NaAsO 2 induced hepatic IR and ferroptosis via methyltransferase-like 14 (METTL14) and YTH domain-containing family protein 2 (YTHDF2)-mediated N6-methyladenosine (m 6 A) of PGC-1α mRNA. In conclusion, NaAsO 2 -mediated PGC-1α suppression was m 6 A methylation-dependent and induced ferroptosis via the PGC-1α/NRF1/GSTK1 pathway in hepatic IR. The data might provide insight into potential targets for diabetes prevention and treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Exposure to Di (2-ethylhexyl) phthalate (DEHP) has been associated with toxic effects of the reproductive system. However, the exact mechanism remains to be elucidated. In this study we explored the testicular toxicity induced by DEHP, and the probable molecular mechanism in the process. In vivo, the results demonstrated that DEHP affected testosterone levels and blood-testosterone barrier (BTB) integrity and caused ferroptosis. We further demonstrated that DEHP up-regulated the expression of p38α, p-p38α, p53, p-p53, SAT1, ALOX15. This view has also been confirmed in TM4 cells. After pre-treatment with fer-1 or si-MAPK14, the expression of either p53, p-p53, SAT1 and ALOX15 up-regulated by MEHP was inhibited in vitro. Interestingly, p38α can prevent the accumulation of lipid ROS, and the production of lipid ROS in turn promoted the expression of p38α, thus forming a feedback loop during the ferroptosis. In this process, a vicious cycle consisting of p38α, p53, SAT1, ALOX15, lipid ROS was involved. This study provides new mechanistic insights into DEHP-induced toxicity of the reproductive system., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Patulin (PAT) is a common mycotoxin, widely found in cereals, seafood, nuts, and especially in fruits and their products. Exposure to this mycotoxin has been reported to induce kidney injury. However, the possible mechanism remains unclear. In our study, short-term high-dose intake of PAT caused acute kidney injury (AKI) in mice. We performed high-throughput transcriptional sequencing to identify differentially expressed genes (DEGs) between the treatment and control groups. The ferroptosis signaling pathway had the highest enrichment, suggesting ferroptosis is involved in PAT-induced AKI. Further, the existence of ferroptosis and autophagy was confirmed by observing the changes of mitochondria morphology and the formation of autophagosomes by electron microscopy. And the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), p62, nuclear receptor coactivator 4 (NCOA4), and ferritin heavy chain 1 (FTH1) were downregulated, whereas acyl-CoA synthase long-chain family member 4 (ACSL4), transferrin (TF), LC3, and ferritin light chain (FTL) expression were upregulated in PAT-exposed mice. These results suggested autophagy-dependent ferroptosis occurred in the animal model. This view has also been confirmed in the human renal tubular epithelial cell (HKC) experiments. Autophagy inhibitor 3-methyladenine (3MA) attenuated PAT-induced ferroptosis and the iron contents in HKC cells. Simultaneous autophagy-dependent ferroptosis can be inhibited by ferroptosis inhibitors ferrostatin-1 (Fer-1) and desferrioxamine (DFO). In general, this study provides a new perspective for exploring the new mechanism of acute kidney injury caused by PAT.

Acrolein is a typical food and environmental pollutant and a risk factor for diabetes. The primary pathogenesis of diabetes is insulin deficiency and resistance. Ferroptosis is an iron-dependent cell death type, accompanying by lipid peroxide accumulation. Here, 25 μM acrolein-induced ferroptosis is observed in mouse pancreatic β-cell MIN6 cells as indicated by ferroptosis-related indicators, including GPX4 exhaustion, lipid peroxides accumulation, and insulin secretion impairment. Additionally, acrolein-induced ferroptosis could be reversed by Ferrostatin-1. Furthermore, endoplasmic reticulum stress (ER stress) is involved in acrolein-induced ferroptosis. The ER stress inhibits the expression of PPARγ, an essential gene in glucose and lipid metabolism, and facilitates lipid peroxide accumulation, leading to MIN6 cells ferroptosis and dysfunction. Moreover, resveratrol, an antioxidant natural product, may relieve ER stress and upregulate PPARγ expression, thereby inhibiting acrolein-induced ferroptosis. Thus, this study demonstrated a new perspective for the cytotoxic mechanism of acrolein on pancreatic β-cell and the protective effect of resveratrol., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Glioma is the most common type of malignant tumor of the nervous system, and aggressiveness and recurrence are major obstacles for treatment. This study is designed to explore the effects of amentoflavone (AF) on glioma, and to investigate the underlying mechanism of the anti-cancer activities of AF., Methods: Cell morphology was recorded under microscopy. Cell viability and cell death ratio were determined by CCK-8 assay and lactate dehydrogenase (LDH) release assay, respectively. Cell cycle progression was assessed by flow cytometry. The levels of iron, MDA (malondialdehyde), lipid ROS, and GSH (reduced glutathione) were assessed by ELISA kit. The cycle-related proteins, ferroptosis-related protein, autophagy-related protein, and the phosphorylation of AMPK, mTOR and p70S6K were analyzed by western blotting. The autophagic flux was observed by transfecting cells with mRFP-GFP-LC3 plasmids. The xenograft murine models were established to analyze the effects of amentoflavone in vivo. The immunohistochemistry assay was performed to analyze the expression of LC3B, Beclin1, ATG5, ATG7, and ferritin heavy chain (FTH)., Results: Our results showed that AF treatment led to reduction in cell viability and cell death. In addition, AF was found to block cell cycle progression in a dose-dependent manner in vitro. Following treatment with AF, the intracellular levels of iron, MDA, and lipid OS were increased, and the levels of GSH and the mitochondrial membrane potential were reduced. In addition, our results showed that AF promoted the autophagic by regulating autophagy-relevant proteins. Our results also showed that the autophagy-induction by AF was associated with regulation of AMPK/mTOR signaling. Mechanistically, the inhibition effects of AF on glioma cell were reversed by DFO, ferreostatin-1 as well as upregulation of FTH. Meanwhile, the FTH levels were increased by compound C and knockdown of ATG7. Moreover, both autophagy inhibitor Baf A1 and knockdown of ATG7 were able to compromising AF-induce ferroptosis and cell death. In vivo, the tumor growth was suppressed by AF in a dose-dependent manner. The level of MDA in the tumor tissue was increased while the level of GSH in tumor tissue was decreased by AF in a dose-dependent manner. Furthermore, the expression of LC3B, Beclin1, ATG5, ATG7 were increased, and the expression of FTH were decreased by AF in a dose-dependent manner in vivo. Conclusion These results demonstrate that AF triggered ferroptosis in autophagy-dependent manner. Our results suggest that AF has the potential to be considered as a novel treatment agent in glioma., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO 2 -induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Exposure to arsenic is a risk factor for nonalcoholic steatohepatitis (NASH). Ferroptosis is a form of regulated cell death defined by the accumulation of lipid peroxidation. In the current study, we observed the occurrence of ferroptosis in arsenic-induced NASH by assessing ferroptosis related hallmarks. In vitro , we found that ferrostatin-1 effectively attenuated the executing of ferroptosis and NASH. Simultaneously, the expression of ACSL4 (acyl-CoA synthetase long-chain family member 4) was upregulated in rat's liver and L-02 cells exposed to arsenic. While, suppression of ACSL4 with rosiglitazone or ACSL4 siRNA remarkably alleviated arsenic-induced NASH and ferroptosis through diminishing 5-hydroxyeicosatetraenoic acid (5-HETE) content. Additionally, Mitofusin 2 (Mfn2), a physical tether between endoplasmic reticulum and mitochondria, has rarely been explored in the ferroptosis. Using Mfn2 siRNA or inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, we found NASH and ferroptosis were obviously mitigated through reducing 5-HETE content. Importantly, Co-IP assay indicated that Mfn2 could interact with IRE1α and promoted the production of 5-HETE, ultimately led to ferroptosis and NASH. Collectively, our data showed that ferroptosis is involved in arsenic-induced NASH. These data provide insightful viewpoints into the mechanism of arsenic-induced NASH. • Ferroptosis is involved in NaAsO 2 -induced nonalcoholic steatohepatitis. • NaAsO 2 -induced ferroptotic cell death depends on the interaction of Mfn2 and IRE1α. • The ACSL4 plays a leading role in the progression of ferroptosis induced by NaAsO 2 via manipulating 5-HETE content. [ABSTRACT FROM AUTHOR]

Di-ethylhexyl phthalate (DEHP) is used as an important plasticizer in a wide range of products such as paints, food packaging, medical devices and children's toys. In recent years, there has been increasing interest in the toxic effects of DEHP on the male reproductive organs, the testicles. Here, we reviewed the basic pathways of testicular damage caused by DEHP. The mechanism involves oxidative stress, ferroptosis, interfering with hypothalamic-pituitary-gonadal axis (HPGA) and testosterone level. We summarized the protective agents that have been shown to be effective in repairing this type of testicular damage in recent years. This provides a new perspective and direction for future research into the health effects and molecular mechanisms of DEHP. • DEHP exposure can lead to testicular tissue damage and spermatogenic dysfunction. • The mechanism of DEHP damage to testes involves oxidative stress, ferroptosis, interfering with HPTA and testosterone level. • We summarized the protective agents that have been proven to be effective in repairing testicular damage caused by DEHP. [ABSTRACT FROM AUTHOR]