Cathepsin B is an executioner of ferroptosis

Nagakannan, Pandian; Islam, Md. Imamul; Conrad, Marcus; Eftekharpour, Eftekhar

doi:10.1016/j.bbamcr.2020.118928

Cited by 59 publications

(42 citation statements)

References 94 publications

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“…Although a cell-free system suggested that POR-mediated lipid peroxidation has potential pore-forming ability ( Yan et al, 2021 ), it seems that POR only partially mediates ferroptosis. Cathepsin B (CTSB) belongs to the family of lysosomal cysteine proteases and has recently been regarded as one of the mediators of ferroptosis through its ability to cause nuclear damage ( Kuang et al, 2020 ; Nagakannan et al, 2021 ). However, the rupture of the lysosomal membrane that leads to CTSB activation is observed in various lethal subroutines, suggesting that CTSB cannot be a specific executor of ferroptosis.…”

Section: Signaling and Process Of Ferroptosismentioning

confidence: 99%

Ferroptosis in infection, inflammation, and immunity

Chen

Kang

Kroemer

et al. 2021

Journal of Experimental Medicine

447

231

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Ferroptosis is a type of regulated necrosis that is triggered by a combination of iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers of ferroptosis can be divided into two categories (biological versus chemical) and activate two major pathways (the extrinsic/transporter versus the intrinsic/enzymatic pathways). Excessive or deficient ferroptotic cell death is implicated in a growing list of physiological and pathophysiological processes, coupled to a dysregulated immune response. This review focuses on new discoveries related to how ferroptotic cells and their spilled contents shape innate and adaptive immunity in health and disease. Understanding the immunological characteristics and activity of ferroptotic death not only illuminates an intersection between cell death and immunity but may also lead to the development of novel treatment approaches for immunopathological diseases.

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Section: Signaling and Process Of Ferroptosismentioning

confidence: 99%

Ferroptosis in infection, inflammation, and immunity

Chen

Kang

Kroemer

et al. 2021

Journal of Experimental Medicine

447

231

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“…It has also been shown to induce mitochondrial dysfunction through its degradation of TFAM resulting in mtROS production, a key NLRP3 activator [ 183 , 184 ]. Cathepsin B has also been implicated in the release of CytC from mitochondria [ 185 ] and ferroptosis [ 186 ]. Therefore, it is possible that the activation of NLRP3, as well as other inflammatory pathways, may be mediated by a variety of intracellular stress signals including cathepsin B-mediated mitochondrial damage and the subsequent release of mitochondrial DAMPs.…”

Section: Vascular Inflammation Mitochondria and Neuroinflammationmentioning

confidence: 99%

Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

Parodi‐Rullán

Javadov

Fossati

2021

Cells

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Alzheimer’s disease (AD) is the most prevalent cause of dementia and is pathologically characterized by the presence of parenchymal senile plaques composed of amyloid β (Aβ) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The accumulation of Aβ also occurs within the cerebral vasculature in over 80% of AD patients and in non-demented individuals, a condition called cerebral amyloid angiopathy (CAA). The development of CAA is associated with neurovascular dysfunction, blood–brain barrier (BBB) leakage, and persistent vascular- and neuro-inflammation, eventually leading to neurodegeneration. Although pathologically AD and CAA are well characterized diseases, the chronology of molecular changes that lead to their development is still unclear. Substantial evidence demonstrates defects in mitochondrial function in various cells of the neurovascular unit as well as in the brain parenchyma during the early stages of AD and CAA. Dysfunctional mitochondria release danger-associated molecular patterns (DAMPs) that activate a wide range of inflammatory pathways. In this review, we gather evidence to postulate a crucial role of the mitochondria, specifically of cerebral endothelial cells, as sensors and initiators of Aβ-induced vascular inflammation. The activated vasculature recruits circulating immune cells into the brain parenchyma, leading to the development of neuroinflammation and neurodegeneration in AD and CAA.

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“…We also identified lysosome damage—which is seldomly mentioned in previous studies of ferroptosis [ 71 ] —via LysoTracker Red DND‐99 and acridine orange (AO) staining. LysoTracker Red DND‐99, a lysosome‐targeted dye containing weakly basic substituents, exhibits a bright red fluorescence after protonation, while AO is a lysosomotropic metachromatic fluorochrome that changes from red to green upon leakage from the lysosome to the cytoplasm.…”

Section: Resultsmentioning

confidence: 92%

A Ferrocene‐Functionalized Covalent Organic Framework for Enhancing Chemodynamic Therapy via Redox Dyshomeostasis

Zhou

Guan

et al. 2021

Small

105

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Chemodynamic therapy (CDT), which induces cell death by decomposing high levels of H2O2 in tumor cells into highly toxic ·OH, is recognized as a promising antineoplastic approach. However, current CDT approaches are often restricted by the highly controlled and upregulated cellular antioxidant defense. To enhance ·OH‐induced cellular damage by CDT, a covalent organic framework (COF)‐based, ferrocene (Fc)‐ and glutathione peroxidase 4 (GPX4) inhibitor‐loaded nanodrug, RSL3@COF–Fc (2b), is fabricated. The obtained 2b not only promotes in situ Fenton‐like reactions to trigger ·OH production in cells, but also attenuates the repair mechanisms under oxidative stress via irreversible covalent GPX4 inhibition. As a result, these two approaches synergistically result in massive lipid peroxide accumulation, subsequent cell damage, and ultimately ferroptosis, while not being limited by intracellular glutathione. It is believed that this research provides a paradigm for enhancing reactive oxygen species‐mediated oncotherapy through redox dyshomeostasis and may provide new insights for developing COF‐based nanomedicine.

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Cathepsin B is an executioner of ferroptosis

Cited by 59 publications

References 94 publications

Ferroptosis in infection, inflammation, and immunity

Ferroptosis in infection, inflammation, and immunity

Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

A Ferrocene‐Functionalized Covalent Organic Framework for Enhancing Chemodynamic Therapy via Redox Dyshomeostasis

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