ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis

He, Feng; Zhang, Peng; Liu, Junlai; Wang, Ruolei; Kaufman, Randal J.; Yaden, Benjamin C.; Karin, Michael

doi:10.1016/j.jhep.2023.03.016

Cited by 127 publications

(37 citation statements)

References 67 publications

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“…Its main biological role is to control the transmembrane exchange of cystine and glutamic acid, and to mediate the entry of cystine into cells, thus providing raw material for intracellular GSH synthesis. Then, GSH may convert lipid peroxidation into non-toxic fatty alcohols, which protect cells from oxidative stress 56 , 57 . The expression of SLC7A11 is dysregulated in many kinds of tumor cells, such as lung cancer, liver cancer, breast cancer and CRC, and plays an important role in the occurrence and development of tumor.…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of Novel Ferroptosis-related Risk Score Signature and Prognostic Prediction Nomogram for Patients with Colorectal Cancer

Liu,

Wang,

et al. 2024

Int. J. Med. Sci.

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Background: Colorectal cancer (CRC) has a high morbidity and mortality. Ferroptosis is a phenomenon in which metabolism and cell death are closely related. The role of ferroptosis-related genes in the progression of CRC is still not clear. Therefore, we screened and validated the ferroptosis-related genes which could determine the prevalence, risk and prognosis of patients with CRC. Methods: We firstly screened differentially expressed ferroptosis-related genes by The Cancer Genome Atlas (TCGA) database. Then, these genes were used to construct a risk-score model using the least absolute shrinkage and selection operator (LASSO) regression algorithm. The function and prognosis of the ferroptosis-related genes were confirmed using multi-omics analysis. The gene expression results were validated using publicly available databases and qPCR. We also used publicly available data and ferroptosis-related genes to construct a prognostic prediction nomogram. Results: A total of 24 differential expressed genes associated with ferroptosis were screened in this study. A three-gene risk score model was then established based on these 24 genes and GPX3, CDKN2A and SLC7A11 were selected. The significant prognostic value of this novel three-gene signature was also assessed. Furthermore, we conducted RT-qPCR analysis on cell lines and tissues, and validated the high expression of CDKN2A, GPX3 and low expression of SLC7A11 in CRC cells. The observed mRNA expression of GPX3, CDKN2A and SLC7A11 was consistent with the predicted outcomes. Besides, eight variables including selected ferroptosis related genes were included to establish the prognostic prediction nomogram for patients with CRC. The calibration plots showed favorable consistency between the prediction of the nomogram and actual observations. Also, the time-dependent AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. Conclusions: The present study constructed and validated a novel ferroptosis-related three-gene risk score signature and a prognostic prediction nomogram for patients with CRC. Also, we screened and validated the ferroptosis-related genes GPX3, CDKN2A, and SLC7A11 which could serve as novel biomarkers for patients with CRC.

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Section: Discussionmentioning

confidence: 99%

Construction and Validation of Novel Ferroptosis-related Risk Score Signature and Prognostic Prediction Nomogram for Patients with Colorectal Cancer

Liu,

Wang,

et al. 2024

Int. J. Med. Sci.

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“…Previous research has demonstrated that ferroptosis is primarily modulated by NRF2, which plays an antioxidant role by controlling SLC7A11 transcription [ 57 ]. Emerging evidence further clarifies that ATF4 and NRF2 coordinately promote transcription of SLC7A11, which block stress-related ferroptosis by controlling glutathione metabolism [ 58 ]. In contrast, ATF3 augments ferroptosis by transcriptionally negatively regulating SLC7A11 expression [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-mediated ferroptosis induced by CARD9 ablation prevents MDSCs-dependent antifungal immunity

Zhang,

Li,

Chen

et al. 2024

Cell Commun Signal

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Background Caspase Recruitment Domain-containing protein 9 (CARD9) expressed in myeloid cells has been demonstrated to play an antifungal immunity role in protecting against disseminated candidiasis. Hereditary CARD9 ablation leads to fatal disseminated candidiasis. However, the myeloid cell types and molecular mechanisms implicated in CARD9 protecting against disseminated candidiasis remain wholly elusive. Methods The role of CARD9 ablation in exacerbating disseminated candidiasis was determined in vivo and in vitro. The molecular mechanism by which CARD9 ablation promotes acute kidney injury in disseminated candidiasis was identified by RNA-sequencing analysis. The expression of mitochondrial proteins and ferroptosis-associated proteins were measured by Quantitative real-time PCR and western blot. Results CARD9 ablation resulted in a reduced proportion of myeloid-derived suppressor cells (MDSCs) and a substantially lower expression of solute carrier family 7 member 11 (SLC7A11) in the kidneys, which increased susceptibility to acute kidney injury and renal ferroptosis during disseminated Candida tropicalis (C. tropicalis) infection. Moreover, CARD9-deficient MDSCs were susceptible to ferroptosis upon stimulation with C. tropicalis, which was attributed to augmented mitochondrial oxidative phosphorylation (OXPHOS) caused by reduced SLC7A11 expression. Mechanistically, C-type lectin receptors (CLRs)-mediated recognition of C. tropicalis promoted the expression of SLC7A11 which was transcriptionally manipulated by the Syk-PKCδ-CARD9-FosB signaling axis in MDSCs. FosB enhanced SLC7A11 transcription by binding to the promoter of SLC7A11 in MDSCs stimulated with C. tropicalis. Mitochondrial OXPHOS, which was negatively regulated by SLC7A11, was responsible for inducing ferroptosis of MDSCs upon C. tropicalis stimulation. Finally, pharmacological inhibition of mitochondrial OXPHOS or ferroptosis significantly increased the number of MDSCs in the kidneys to augment host antifungal immunity, thereby attenuating ferroptosis and acute kidney injury exacerbated by CARD9 ablation during disseminated candidiasis. Conclusions Collectively, our findings show that CARD9 ablation enhances mitochondria-mediated ferroptosis in MDSCs, which negatively regulates antifungal immunity. We also identify mitochondria-mediated ferroptosis in MDSCs as a new molecular mechanism of CARD9 ablation-exacerbated acute kidney injury during disseminated candidiasis, thus targeting mitochondria-mediated ferroptosis is a novel therapeutic strategy for acute kidney injury in disseminated candidiasis.

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“…P53 promotes apoptosis [ 73 ] and ferroptosis [ 74 , 75 ]. SLC7A11 inhibits ferroptosis [ 76 ] and promotes disulfidptosis [ 54 ]. Ca 2+ up-regulation promotes autophagy and inhibits apoptosis [ 70 ].…”

Section: Molecular Mechanisms Of Different Cell Death Pathwaysmentioning

confidence: 99%

Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

Zhou,

Liu,

Wan

et al. 2024

J Hematol Oncol

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Tumor is a local tissue hyperplasia resulted from cancerous transformation of normal cells under the action of various physical, chemical and biological factors. The exploration of tumorigenesis mechanism is crucial for early prevention and treatment of tumors. Epigenetic modification is a common and important modification in cells, including DNA methylation, histone modification, non-coding RNA modification and m6A modification. The normal mode of cell death is programmed by cell death-related genes; however, recent researches have revealed some new modes of cell death, including pyroptosis, ferroptosis, cuproptosis and disulfidptosis. Epigenetic regulation of various cell deaths is mainly involved in the regulation of key cell death proteins and affects cell death by up-regulating or down-regulating the expression levels of key proteins. This study aims to investigate the mechanism of epigenetic modifications regulating pyroptosis, ferroptosis, cuproptosis and disulfidptosis of tumor cells, explore possible triggering factors in tumor development from a microscopic point of view, and provide potential targets for tumor therapy and new perspective for the development of antitumor drugs or combination therapies.

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ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis

Cited by 127 publications

References 67 publications

Construction and Validation of Novel Ferroptosis-related Risk Score Signature and Prognostic Prediction Nomogram for Patients with Colorectal Cancer

Construction and Validation of Novel Ferroptosis-related Risk Score Signature and Prognostic Prediction Nomogram for Patients with Colorectal Cancer

Mitochondria-mediated ferroptosis induced by CARD9 ablation prevents MDSCs-dependent antifungal immunity

Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

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