IRF1/ZNF350/GPX4-mediated ferroptosis of renal tubular epithelial cells promote chronic renal allograft interstitial fibrosis

Zhang, Yao; Zhang, Jianjian; Feng, Dengyuan; Zhou, Hai; Gui, Zeping; Zheng, Ming; Zhou, Hang; Wang, Zijie; Wang, Zengjun; Gu, Min; Tan, Ruoyun

doi:10.1016/j.freeradbiomed.2022.11.002

Cited by 14 publications

(9 citation statements)

References 72 publications

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“…Preparation of HUVECs for transmission electron microscopy (TEM) analysis was as described 31 . The prepared electron microscope samples were processed and scanned using TEM (FEI Tecnai G2) at the Analysis and Testing Center, Nanjing Medical University.…”

Section: Methodsmentioning

confidence: 99%

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Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy

Feng,

Gui,

et al. 2024

Clinical & Translational Med

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BackgroundRenal allograft interstitial fibrosis/tubular atrophy (IF/TA) constitutes the principal histopathological characteristic of chronic allograft dysfunction (CAD) in kidney‐transplanted patients. While renal vascular endothelial‐mesenchymal transition (EndMT) has been verified as an important contributing factor to IF/TA in CAD patients, its underlying mechanisms remain obscure. Through single‐cell transcriptomic analysis, we identified Rictor as a potential pivotal mediator for EndMT. This investigation sought to elucidate the role of Rictor/mTORC2 signalling in the pathogenesis of renal allograft interstitial fibrosis and the associated mechanisms.MethodsThe influence of the Rictor/mTOR2 pathway on renal vascular EndMT and renal allograft fibrosis was investigated by cell experiments and Rictor depletion in renal allogeneic transplantation mice models. Subsequently, a series of assays were conducted to explore the underlying mechanisms of the enhanced mitophagy and the ameliorated EndMT resulting from Rictor knockout.ResultsOur findings revealed a significant activation of the Rictor/mTORC2 signalling in CAD patients and allogeneic kidney transplanted mice. The suppression of Rictor/mTORC2 signalling alleviated TNFα‐induced EndMT in HUVECs. Moreover, Rictor knockout in endothelial cells remarkably ameliorated renal vascular EndMT and allograft interstitial fibrosis in allogeneic kidney transplanted mice. Mechanistically, Rictor knockout resulted in an augmented BNIP3‐mediated mitophagy in endothelial cells. Furthermore, Rictor/mTORC2 facilitated the MARCH5‐mediated degradation of BNIP3 at the K130 site through K48‐linked ubiquitination, thereby regulating mitophagy activity. Subsequent experiments also demonstrated that BNIP3 knockdown nearly reversed the enhanced mitophagy and mitigated EndMT and allograft interstitial fibrosis induced by Rictor knockout.ConclusionsConsequently, our study underscores Rictor/mTORC2 signalling as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis progression, exerting its impact through regulating BNIP3‐mediated mitophagy. This insight unveils a potential therapeutic target for mitigating renal allograft interstitial fibrosis.

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Section: Methodsmentioning

confidence: 99%

“…Renal allograft histological pathology analyses were evaluated by Masson trichrome staining and hematoxylin and eosin (H&E) as previously described 31 . HE staining was utilized to assess allograft structure changes, while Masson staining was employed to assess renal interstitial fibrosis degree.…”

Section: Methodsmentioning

confidence: 99%

Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy

Feng,

Gui,

et al. 2024

Clinical & Translational Med

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“…Thus, TLR4/Trif-dependent signaling pathway provides additional insight into the ferroptotic pathway, and could represent a new therapeutic target in mitigating IRI after organ transplantation. Most recently, Zhang and associates [ 73 ] conducted a clinical investigation involving 20 patients who suffered chronic renal allograft dysfunction. Following biopsy and nephrectomy of the transplanted kidneys, immunohistochemical staining revealed accumulation of lipid peroxidation, which was evidenced by increased renal expression of 4-HNE (a product of lipid peroxidation) compared to normal kidney tissues.…”

Section: Cell Death In Ischemia–reperfusion Injurymentioning

confidence: 99%

Cellular and molecular mechanisms of cell damage and cell death in ischemia–reperfusion injury in organ transplantation

Dugbartey

2024

Mol Biol Rep

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Ischemia–reperfusion injury (IRI) is a critical pathological condition in which cell death plays a major contributory role, and negatively impacts post-transplant outcomes. At the cellular level, hypoxia due to ischemia disturbs cellular metabolism and decreases cellular bioenergetics through dysfunction of mitochondrial electron transport chain, causing a switch from cellular respiration to anaerobic metabolism, and subsequent cascades of events that lead to increased intracellular concentrations of Na+, H+ and Ca2+ and consequently cellular edema. Restoration of blood supply after ischemia provides oxygen to the ischemic tissue in excess of its requirement, resulting in over-production of reactive oxygen species (ROS), which overwhelms the cells’ antioxidant defence system, and thereby causing oxidative damage in addition to activating pro-inflammatory pathways to cause cell death. Moderate ischemia and reperfusion may result in cell dysfunction, which may not lead to cell death due to activation of recovery systems to control ROS production and to ensure cell survival. However, prolonged and severe ischemia and reperfusion induce cell death by apoptosis, mitoptosis, necrosis, necroptosis, autophagy, mitophagy, mitochondrial permeability transition (MPT)-driven necrosis, ferroptosis, pyroptosis, cuproptosis and parthanoptosis. This review discusses cellular and molecular mechanisms of these various forms of cell death in the context of organ transplantation, and their inhibition, which holds clinical promise in the quest to prevent IRI and improve allograft quality and function for a long-term success of organ transplantation.

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“…Their investigations revealed that luteolin upregulates HIC-1, which is a transcriptional repressor in colon cancer. Upon HIC-1 activation by luteolin, the transcriptional activity of GPX4 is decreased, which subsequently leads to the ferroptosis of cancer cells (Zheng, Li, et al, 2023). Therefore, luteolin might induce ferroptosis in cancer cells by affecting transcription factors that regulate amino acid metabolism and iron ions.…”

Section: Luteolinmentioning

confidence: 99%

“…In vitro studies using HCT116 and SW480 cells, as well as in vivo experiments with a xenograft model in mice, demonstrate that the combined treatment effectively inhibits cancer cell viability and proliferation. The synergistic effects were observed at a 2:1 ratio of luteolin (25 μM) to erastin (12.5 μM) (Zheng, Li, et al, 2023). Gemcitabine is a chemotherapy drug commonly used in the treatment of various cancers, including pancreatic cancer.…”

Section: Carnosic Acidmentioning

confidence: 99%

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

Zhang,

Xie

2024

Phytotherapy Research

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In recent years, heightened interest surrounds the exploration of natural phenols as potential agents for cancer therapy, specifically by inducing ferroptosis, a unique form of regulated cell death characterized by iron‐dependent lipid peroxidation. This review delves into the roles of key natural phenols, flavonoids, phenolic acids, curcumin, and stilbenes, in modulating ferroptosis and their underlying mechanisms. Emphasizing the significance of amino acid, lipid, and iron metabolism, the study elucidates the diverse pathways through which these phenols regulate ferroptosis. Notably, curcumin, a well‐known polyphenol, exhibits multifaceted interactions with cellular components involved in ferroptosis regulation, providing a distinctive therapeutic avenue. Stilbenes, another phenolic class, demonstrate promising potential in influencing lipid metabolism and iron‐dependent processes, contributing to ferroptotic cell death. Understanding the intricate interplay between these natural phenols and ferroptosis not only illuminates complex cellular regulatory networks but also unveils potential avenues for novel cancer therapies. Exploring these compounds as inducers of ferroptosis presents a promising strategy for targeted cancer treatment, capitalizing on the delicate balance between cellular metabolism and regulated cell death mechanisms. This article synthesizes current knowledge, aiming to stimulate further research into the therapeutic potential of natural phenols in the context of ferroptosis‐mediated cancer therapy.

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IRF1/ZNF350/GPX4-mediated ferroptosis of renal tubular epithelial cells promote chronic renal allograft interstitial fibrosis

Cited by 14 publications

References 72 publications

Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy

Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy

Cellular and molecular mechanisms of cell damage and cell death in ischemia–reperfusion injury in organ transplantation

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

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