Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases

Li, Jinghan; Zheng, Sujuan; Fan, Yumei; Tan, Ke

doi:10.1038/s41419-023-06144-w

Cited by 22 publications

(7 citation statements)

References 308 publications

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“…Nrf2 is identified as an important regulator for the expression of a series of antioxidant genes, including GSH homeostasis, and GPX4 activity ( 29 ). To explore the role of Nrf2 in BVDV-induced ferroptosis, we focused on the antioxidative genes implicated in negatively regulating ferroptosis, including SLC7A11 and GPX4 ( 30 ).…”

Section: Resultsmentioning

confidence: 99%

Mitochondria-mediated ferroptosis contributes to the inflammatory responses of bovine viral diarrhea virus (BVDV) in vitro

Li,

Zhao,

Zhang

et al. 2024

J Virol

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Bovine viral diarrhea virus (BVDV) belongs to the family Flaviviridae and includes two biotypes in cell culture: cytopathic (CP) or non-cytopathic (NCP) effects. Ferroptosis is a non-apoptotic form of programmed cell death that contributes to inflammatory diseases. However, whether BVDV induces ferroptosis and the role of ferroptosis in viral infection remain unclear. Here, we provide evidence that both CP and NCP BVDV can induce ferroptosis in Madin-Darby bovine kidney cells at similar rate. Mechanistically, biotypes of BVDV infection downregulate cytoplasmic and mitochondrial GPX4 via Nrf2-GPX4 pathway, thereby resulting in lethal lipid peroxidation and promoting ferroptosis. In parallel, BVDV can degrade ferritin heavy chain and mitochondrial ferritin via NCOA4-mediated ferritinophagy to promote the accumulation of Fe 2+ and initiate ferroptosis. Importantly, CP BVDV-induced ferroptosis is tightly associated with serious damage of mitochondria and hyperactivation of inflammatory responses. In contrast, mild or unapparent damage of mitochondria and slight inflammatory responses were detected in NCP BVDV-infected cells. More importantly, different mitophagy pathways in response to mitochondria damage by both biotypes of BVDV are involved in inflammatory responses. Overall, this study is the first to show that mitochondria may play key roles in mediating ferroptosis and inflammatory responses induced by biotypes of BVDV in vitro . IMPORTANCE Bovine viral diarrhea virus (BVDV) threatens a wide range of domestic and wild cattle population worldwide. BVDV causes great economic loss in cattle industry through its immunosuppression and persistent infection. Despite extensive research, the mechanism underlying the pathogenesis of BVDV remains elusive. Our data provide the first direct evidence that mitochondria-mediated ferroptosis and mitophagy are involved in inflammatory responses in both biotypes of BVDV-infected cells. Importantly, we demonstrate that the different degrees of injury of mitochondria and inflammatory responses may attribute to different mitophagy pathways induced by biotypes of BVDV. Overall, our findings uncover the interaction between BVDV infection and mitochondria-mediated ferroptosis, which shed novel light on the physiological impacts of ferroptosis on the pathogenesis of BVDV infection, and provide a promising therapeutic strategy to treat this important infectious disease with a worldwide distribution.

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Section: Resultsmentioning

confidence: 99%

Mitochondria-mediated ferroptosis contributes to the inflammatory responses of bovine viral diarrhea virus (BVDV) in vitro

Li,

Zhao,

Zhang

et al. 2024

J Virol

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“…Ferroptosis, characterized by iron-dependent LPO, is inuenced by various cellular metabolic pathways encompassing redox homeostasis, iron metabolism, mitochondrial function, and the metabolism of amino acids, lipids, and carbohydrates. 39 Given the pivotal role of iron in ferroptosis, we studied the iron chelation capabilities of Cur-PDA NPs, particularly toward Fe 2+ and Fe 3+ . Fe 3+ forms a pink complex with 2,2 0 -bipyridine, known as the 2,2 0 -bipyridine-Fe 3+ complex.…”

Section: Iron Chelating Ability Of Cur-pda Npsmentioning

confidence: 99%

Curcumin–polydopamine nanoparticles alleviate ferroptosis by iron chelation and inhibition of oxidative stress damage

Lei,

Yuan,

Yang

et al. 2024

RSC Adv.

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“…The interaction of aspirin with many other iron metabolic pathways, including the effects of aspirin on the expression of iron transport and storage proteins and metabolic pathways such as ferroptosis, which is a newly identified programmed cell death involving iron, free radicals and peroxidation of lipids of the cell membrane are attracting the interest of many investigators in almost all diseases [177][178][179][180][181][182][183]. In particular, several studies have suggested that aspirin is involved in the modulation of ferroptosis in many diseases, including chronic kidney disease and cancer [183][184][185][186]. Most importantly, the modulation of ferroptosis by aspirin has been suggested as a mechanism for the treatment of different untreated cancers, anticancer drug resistance, and metastasis [187][188][189][190][191][192][193][194].…”

Section: Interactions Of Aspirin (Acetylsalicylic Acid) and Its Glucu...mentioning

confidence: 99%

“…A major unexplored area of great importance in pharmacology and medicine is the effects of aspirin and ACM, as well as their iron complexes, on ferroptosis, which is a recently identified type of programmed cell death based on iron-catalysed lipid peroxidation damage of cell membranes [179][180][181][182][183][184]. Ferroptosis has been identified in almost all diseases, including cancer and neurodegeneration [179][180][181][182][183][184][185][186][187][188][189][190]. Several preliminary investigations have already implicated aspirin in the process of ferroptosis via different mechanisms [192][193][194].…”

Section: Future Studies and Limitations On The Role Of Aspirin In Iro...mentioning

confidence: 99%

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

Kontoghiorghes

2024

IJMS

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Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75–100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM.

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Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases

Cited by 22 publications

References 308 publications

Mitochondria-mediated ferroptosis contributes to the inflammatory responses of bovine viral diarrhea virus (BVDV) in vitro

Mitochondria-mediated ferroptosis contributes to the inflammatory responses of bovine viral diarrhea virus (BVDV) in vitro

Curcumin–polydopamine nanoparticles alleviate ferroptosis by iron chelation and inhibition of oxidative stress damage

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites

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