Ferroptosis, necroptosis and cuproptosis: Novel forms of regulated cell death in diabetic cardiomyopathy

Ke, Dan; Zhang, Zhen; Liu, Jieting; Chen, Peijian; Li, Jialing; Sun, Xun; Chu, Yanhui; Li, Luxin

doi:10.3389/fcvm.2023.1135723

Cited by 18 publications

(5 citation statements)

References 137 publications

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“…35,36 Furthermore Cuproptosis affects the course of Diabetic cardiomyopathy by destroying mitochondrial structure and function. 37 These ndings suggest that there may be underling correlation between CNN1 and AD through copper metabolism and Cuproptosis. But further studies are needed to clarify the speci c regulatory mechanisms.…”

Section: Discussionmentioning

confidence: 92%

Identification of cuproptosis-related biomarkers in aortic dissection：new insights from bioinformatic analysis

Mutailipu,

Zhang,

Ding

et al. 2023

Preprint

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Objective: Aortic dissection (AD) is a cardiovascular disease with a high mortality rate. And the mechanisms of AD are still poorly understood. Cuproptosis is a novel form of programmed cell death that may contributes to occurrence and development of various cardiovascular disease. Therefore, we intend to explore the potential association between cuproptosis-related genes (CRGs) and AD to provide a new biomarker for the treatment and prognosis of AD. Methods: CRGs were obtained from previous literature. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were used to explore the correlation between AD and CRGs. The RNA-seq dataset GSE153434 was used for screening differentially expressed CRGs (DECRGs) between AD and normal group; LASSO and RF machine learning algorithms were used to identify biomarker CRGs and receiver operating characteristic (ROC) curves were used to assess diagnostic efficacy. PPI network was constructed to reveal the interaction between marker CRGs and core CRGs. Subsequent single-gene GSEA and GSVA were performed to explore the function of biomarker CRGs; The mRNA-miRNA-lncRNA network were built to explore the regulatory relationship based on the marker genes. Potential marker CRGs targeted drugs were obtained from Drug Gene Interaction Database (DGIdb). Finally, single-Cell RNA-Seq dataset GSE213740 was used for verification of marker genes distribution and expression in different cell types of aortic tissue.; The RNA-seq dataset GSE52093 was used as validation set for marker genes. Results: First we found potential correlation between AD and CRGs. Then 10 differentially expressed CRGs were obtained from GSE153434, comprising 6 upregulated genes (TOP1M, SLC7A5, WDR12, MAD2L2, LDLR, and SHMT2) and 4 downregulated genes (FZD8, MPC1, CNN1, and N6AMT1). Subsequently, we used LASSO to identify 7 optimal biomarker DECRGs (TOP1M, WDR12, LDLR, FZD8, MPC1, CNN1, and N6AMT1). Then RF model and ROC curves both indicated diagnostic capabilities of those marker genes. PPI network analysis revealed wide interactions between those marker CRGs and core CRGs. Moreover, GSEA and GSVA of marker genes mainly enriched in pivotal pathways related to AD and cuproptosis. Through a drug-gene interaction exploration, we pinpointed potential drugs targeting LDLR, TOP1MT, FZD8 and N6AMT1. Furthermore, the ceRNA network around the 7 marker genes unveiled their regulatory associations with 94 miRNAs and 292 lncRNAs including miR-27a, let-7b, XIST and PVT1. Using Single-cell RNA-seq data from GSE213740, we corroborated the distribution and expression patterns of these marker genes across diverse cell types in aortic tissue. Lastly validation dataset GSE52093 showed that FZD8, MPC1, CNN1 and N6AMT1 expression were consistent with the GSE153434 dataset. Conclusion: Our study systematically illustrates the potential relationship between cuproptosis and AD. We identified several biomarker genes including CNN1, MPC1 and LDLR, which were involved in various pathways related to AD progression. Our findings may provide new insights in diagnosis and clinical treatment strategies for AD.

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Section: Discussionmentioning

confidence: 92%

Identification of cuproptosis-related biomarkers in aortic dissection：new insights from bioinformatic analysis

Mutailipu,

Zhang,

Ding

et al. 2023

Preprint

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“…In particular the metabolic flux through glycolysis is partitioned [ 43 – 45 ], and mitochondrial bioenergetics and OxPhox are impaired, as well as lipid metabolism [ 43 , 46 – 48 ]. Moreover, accumulative researches have been demonstrated that cuproptosis play an important role as regulators of cell metabolism [ 49 – 51 ]. Therefore, this study conducted comprehensive analysis of the role of cuproptosis in ccRCC.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis uncovers clinical, immunological, and pharmacogenomic implications of cuproptosis in clear cell renal cell carcinoma

Zhu

Wang

et al. 2023

Eur J Med Res

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Objective The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective. Methods This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation. Results Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients’ survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group. Conclusion Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.

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“…Ferroptosis has been identified in many pathological conditions, including cancer, COVID-19, and many other infectious, kidney, cardiac, and neurodegenerative diseases [ 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 ]. A different form of cell death with similar effects to ferroptosis is cuproptosis, where copper instead of iron is implicated in programmed cell death [ 205 , 206 , 207 , 208 , 209 , 210 , 211 ]. The inhibition by L1 of both iron- and copper-induced oxidative stress toxicity, is another unique property of the drug, which can be utilised for the design of new strategies and the development of new pharmaceuticals for the control of both ferroptosis and cuproptosis, which have been recognised in many diseases ( Figure 5 ).…”

Section: The High Clinical Antioxidant Potential Of Deferipronementioning

confidence: 99%

The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases

Kontoghiorghes¹

2023

Pharmaceuticals

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The iron chelating orphan drug deferiprone (L1), discovered over 40 years ago, has been used daily by patients across the world at high doses (75–100 mg/kg) for more than 30 years with no serious toxicity. The level of safety and the simple, inexpensive synthesis are some of the many unique properties of L1, which played a major role in the contribution of the drug in the transition of thalassaemia from a fatal to a chronic disease. Other unique and valuable clinical properties of L1 in relation to pharmacology and metabolism include: oral effectiveness, which improved compliance compared to the prototype therapy with subcutaneous deferoxamine; highly effective iron removal from all iron-loaded organs, particularly the heart, which is the major target organ of iron toxicity and the cause of mortality in thalassaemic patients; an ability to achieve negative iron balance, completely remove all excess iron, and maintain normal iron stores in thalassaemic patients; rapid absorption from the stomach and rapid clearance from the body, allowing a greater frequency of repeated administration and overall increased efficacy of iron excretion, which is dependent on the dose used and also the concentration achieved at the site of drug action; and its ability to cross the blood–brain barrier and treat malignant, neurological, and microbial diseases affecting the brain. Some differential pharmacological activity by L1 among patients has been generally shown in relation to the absorption, distribution, metabolism, elimination, and toxicity (ADMET) of the drug. Unique properties exhibited by L1 in comparison to other drugs include specific protein interactions and antioxidant effects, such as iron removal from transferrin and lactoferrin; inhibition of iron and copper catalytic production of free radicals, ferroptosis, and cuproptosis; and inhibition of iron-containing proteins associated with different pathological conditions. The unique properties of L1 have attracted the interest of many investigators for drug repurposing and use in many pathological conditions, including cancer, neurodegenerative conditions, microbial conditions, renal conditions, free radical pathology, metal intoxication in relation to Fe, Cu, Al, Zn, Ga, In, U, and Pu, and other diseases. Similarly, the properties of L1 increase the prospects of its wider use in optimizing therapeutic efforts in many other fields of medicine, including synergies with other drugs.

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Ferroptosis, necroptosis and cuproptosis: Novel forms of regulated cell death in diabetic cardiomyopathy

Cited by 18 publications

References 137 publications

Identification of cuproptosis-related biomarkers in aortic dissection：new insights from bioinformatic analysis

Identification of cuproptosis-related biomarkers in aortic dissection：new insights from bioinformatic analysis

Multi-omics analysis uncovers clinical, immunological, and pharmacogenomic implications of cuproptosis in clear cell renal cell carcinoma

The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases

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