Flavonoid 4,4′-dimethoxychalcone induced ferroptosis in cancer cells by synergistically activating Keap1/Nrf2/HMOX1 pathway and inhibiting FECH

Yang, Changmei; Wang, Tianxiang; Zhao, Yujiao; Meng, Xianbin; Ding, Wenxi; Wang, Qingtao; Liu, Chongdong; Deng, Haiteng

doi:10.1016/j.freeradbiomed.2022.06.010

Cited by 41 publications

(22 citation statements)

References 46 publications

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“…Because HMOX1 is a target gene of nuclear factor erythroid 2‐related factor 2 (NRF2), [ 37 ] and because NRF2 mRNA expression was significantly increased after iCoDMSN treatment (Figure 5C, p < 0.01), we then asked whether this NRF2 enhancement mediated the upregulation of HMOX1. To confirm this speculation, we initially performed western blotting and immunofluorescence experiments and discovered that iCoDMSNs increased NRF2 expression in 4T1 cells ( Figure A,B and Figures S26 and S27, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

“…To more deeply understand the ferroptosis induced by iCoDMSNs, we examined the proteomic data and found that HMOX1, an enzyme that degrades heme into biliverdin to release carbon monoxide and Fe 2+ , [ 37 ] was found to be the most upregulated molecule (Figure 4C). The enhanced expression of HMOX1 was successively verified by immunofluorescence ( Figure A and Figure S22, Supporting Information) and western blotting (Figure 5B and Figure S23, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

“…Because HMOX1 is a target gene of nuclear factor erythroid 2-related factor 2 (NRF2), [37] and because NRF2 mRNA expression was significantly increased after iCoDMSN treatment (Figure 5C, p < 0.01), we then asked whether this NRF2 enhancement mediated the upregulation of HMOX1. To confirm this speculation, we initially performed western expression of HMOX1 was dramatically reduced (Figure 6C and Figure S28, Supporting Information), in accordance with the influence of NRF2 suppression in adipose-derived mesenchymal stem cells.…”

Section: Initiation Of Ferroptosis By Icodmsns By Disturbance Of the ...mentioning

confidence: 99%

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Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization

Zhao

Chen

Xiong

et al. 2023

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High cobalt (Co) levels in tumors are associated with good clinical prognosis. An anticancer regimen that increases intratumoral Co through targeted nanomaterial delivery is proposed in this study. Bovine serum albumin and cobalt dichloride are applied to prepare cobaltous oxide nanodots using a facile biomineralization strategy. After iRGD peptide conjugation, the nanodots are loaded into dendritic mesoporous silica nanoparticles, generating a biocompatible product iCoDMSN. This nanocomposite accumulates in tumors after intravenous injection by deep tissue penetration and can be used for photoacoustic imaging. Proteomics research and molecular biology experiments reveal that iCoDMSN is a potent ferroptosis inducer in cancer cells. Mechanistically, iCoDMSNs upregulate heme oxygenase 1 (HMOX1), which increases transferrin receptors and reduces solute carrier family 40 member 1 (SLC40A1), resulting in Fe2+ accumulation and ferroptosis initiation. Furthermore, upregulated nuclear factor erythroid 2‐related factor 2 (NRF2), arising from the reduction in Kelch‐like ECH‐associated protein 1 (KEAP1) expression, is responsible for HMOX1 enhancement after iCoDMSN treatment. Owing to intensified ferroptosis, iCoDMSN acts as an efficient radiotherapy enhancer to eliminate cancer cells in vitro and in vivo. This study demonstrates a versatile Co‐based nanomaterial that primes ferroptosis by expanding the labile iron pool in cancer cells, providing a promising tumor radiotherapy sensitizer.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Initiation Of Ferroptosis By Icodmsns By Disturbance Of the ...mentioning

confidence: 99%

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Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization

Zhao

Chen

Xiong

et al. 2023

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“…FECH is the last enzyme in heme biosynthesis pathway. Inhibited FECH caused iron overload in cancer cells and triggered iron concentration, thereby inhibiting cancer cell growth [ 24 ]. In addition, the RAS/MEK pathway increased PpIX accumulation in cancer cells by regulating the FECH activity mechanism, which would facilitate precise recognition of tumor boundaries and small satellite tumors [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

FECH Expression Correlates with the Prognosis and Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma

Zhong

Luo

et al. 2022

Journal of Oncology

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Background. Clear cell renal cell carcinoma (ccRCC) is, by far, the most prevalent and fatal kind of kidney cancer. Ferrochelatase (FECH) is an enzyme that performs a significant function in the onset and progression of many distinct kinds of malignant tumors. Nevertheless, its predictive usefulness in renal clear cell carcinoma (RCC) has not yet been fully investigated. Methods. FECH expression in ccRCC and healthy adjoining tissues was primarily screened utilizing data sourced from The Cancer Genome Atlas (TCGA) and subsequently validated using data from an independent cohort derived from the Gene Expression Omnibus (GEO) and the Human Protein Atlas HPA databases. The relationship among FECH expression, clinicopathological parameters, and overall survival (OS) was assessed utilizing multivariate analysis and Kaplan–Meier survival curves. Additionally, the protein networks with FECH interaction were constructed with the aid of the online Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Gene ontology (GO) analysis, and gene set enrichment analysis (GSEA) were conducted based on TCGA data, and a single-sample GSEA was utilized to explore the link between FECH expression and the infiltration status of immune cells in the tumor. The Gene Expression Profiling Interactive Analysis (GEPIA) and TIMER databases were utilized to investigate the relationships of FECH expression with the infiltrating immune cells and the matching gene marker sets. Results. FECH expression was shown to be substantially lowered in ccRCC tumors as opposed to that observed in normal tissues ( p < 0.05 ). Lower levels of FECH expression were shown to have a strong association with higher grades of cancer and more advanced TNM stages. The findings of multivariate and univariate analyses illustrated that the OS in patients with ccRCC with low FECH expression is shorter in contrast with that in the high FECH expression group ( p < 0.05 ). It was discovered that CPOX and frataxin are key proteins that interact with FECH. ccRCC with FECH deficiency was linked to the lack of infiltrating immune cells and their respective marker sets, which included CD4+ T cells. Conclusion. In ccRCC, decreased FECH expression was linked to disease progression, unfavorable prognosis, and impaired immune cell infiltration.

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“…In terms of mechanism, this chalcone compound promoted the expression of TFR and DMT1 by up-regulating caveolin-1, resulting in intracellular iron and ROS accumulation. Furthermore, 4,4′-dimethoxychalcone played an antitumor role by promoting ferroptosis in cancer cells . 4,4′-Dimethoxychalcone could separate NRF2 from Keap1 by promoting the degradation of Keap1, thus increasing the nuclear translocation of NRF2 and up-regulating the expression of HO-1.…”

Section: Natural Flavonoids Targeting Ferroptosismentioning

confidence: 99%

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

Zhou

Zhang

2023

J. Agric. Food Chem.

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Flavonoids are a class of bioactive phytochemicals containing a core 2-phenylchromone skeleton and are widely found in fruits, vegetables, and herbs. Such natural compounds have gained significant attention due to their various health benefits. Ferroptosis is a recently discovered unique iron-dependent mode of cell death. Unlike traditional regulated cell death (RCD), ferroptosis is associated with excessive lipid peroxidation on cellular membranes. Accumulating evidence suggests that this form of RCD is involved in a variety of physiological and pathological processes. Notably, multiple flavonoids have been shown to be effective in preventing and treating diverse human diseases by regulating ferroptosis. In this review, we introduce the key molecular mechanisms of ferroptosis, including iron metabolism, lipid metabolism, and several major antioxidant systems. Additionally, we summarize the promising flavonoids targeting ferroptosis, which provides novel ideas for the management of diseases such as cancer, acute liver injury, neurodegenerative diseases, and ischemia/reperfusion (I/R) injury.

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Flavonoid 4,4′-dimethoxychalcone induced ferroptosis in cancer cells by synergistically activating Keap1/Nrf2/HMOX1 pathway and inhibiting FECH

Cited by 41 publications

References 46 publications

Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization

Clustered Cobalt Nanodots Initiate Ferroptosis by Upregulating Heme Oxygenase 1 for Radiotherapy Sensitization

FECH Expression Correlates with the Prognosis and Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

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