Redox Biology最新文献

{"title":"Lycopene alleviates age-related cognitive deficit via activating liver-brain fibroblast growth factor-21 signalling","authors":"Jia Wang ,&nbsp;Lu Li ,&nbsp;Li Li ,&nbsp;Yuqi Shen ,&nbsp;Fubin Qiu","doi":"10.1016/j.redox.2024.103363","DOIUrl":"10.1016/j.redox.2024.103363","url":null,"abstract":"<div><div>Brain function is linked with many peripheral tissues, including the liver, where hepatic fibroblast growth factor 21 (FGF21) mediates communication between the liver and brain. Lycopene (LYC), a naturally occurring carotenoid, posses multiple health-promoting properties, including neuroprotective function. Here, we investigated the effects of LYC on age-related memory impairment and the relative contribution of liver-brain FGF21 signaling in these process. The results showed that after treatment with LYC for 3 months, brain aging and age-related cognitive deficits were effectively managed. In addition, LYC ameliorated neuronal degeneration, mitochondrial dysfunction and synaptic damage, and promoted synaptic vesicle fusion in 18-month-old mice. Notably, LYC activated liver-brain FGF21 signalling in aging mice. Whereas all these central effects of LYC were negated by blocking FGF21 via <em>i. v.</em> injection of adeno-associated virus in aging mice. Furthermore, recombinant FGF21 elevated mitochondrial ATP levels and enhanced synaptic vesicle fusion in mouse hippocampal HT-22 cells, which promoted neurotransmitter release. Additionally, we co-cultured hepatocytes and neurons in Transwell and found that LYC enhanced hepatocytes’ support for neurons. This support included improved cell senescence, enhanced mitochondrial function, and increased axon length in co-cultured neurons. In conclusion, LYC protects against age-related cognitive deficit, partly explained by activating liver-brain FGF21 signalling, hence promoting neurotransmitters release via increasing mitochondrial ATP levels and enhancing synaptic vesicle fusion. These findings revealed that FGF21 could be a potential therapeutical target in nutritional intervention strategies to improve cognitive damage caused by aging and age-related neurodegenerative diseases.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103363"},"PeriodicalIF":10.7,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003410/pdfft?md5=1a30321819a371ddb1297cf4e7a62a35&pid=1-s2.0-S2213231724003410-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA-HMG incites colorectal cancer cells to chemoresistance via repressing p53-mediated ferroptosis","authors":"Zechang Xin ,&nbsp;Chenyu Hu ,&nbsp;Chunfeng Zhang ,&nbsp;Ming Liu ,&nbsp;Juan Li ,&nbsp;Xiaoyan Sun ,&nbsp;Yang Hu ,&nbsp;Xiaofeng Liu ,&nbsp;Kun Wang","doi":"10.1016/j.redox.2024.103362","DOIUrl":"10.1016/j.redox.2024.103362","url":null,"abstract":"<div><p>Upon chemotherapy, excessive reactive oxygen species (ROS) often lead to the production of massive lipid peroxides in cancer cells and induce cell death, namely ferroptosis. The elimination of ROS is pivotal for tumor cells to escape from ferroptosis and acquire drug resistance. Nevertheless, the precise functions of long non-coding RNAs (lncRNAs) in ROS metabolism and tumor drug-resistance remain elusive. In this study, we identify LncRNA-HMG as a chemoresistance-related lncRNA in colorectal cancer (CRC) by high-throughput screening. Abnormally high expression of LncRNA-HMG predicts poorer prognosis in CRC patients. Concurrently, we found that LncRNA-HMG protects CRC cells from ferroptosis upon chemotherapy, thus enhancing drug resistance of CRC cells. LncRNA-HMG binds to p53 and facilitates MDM2-mediated degradation of p53. Decreased p53 induces upregulation of SLC7A11 and VKORC1L1, which contribute to increase the supply of reducing agents and eliminate excessive ROS. Consequently, CRC cells escape from ferroptosis and acquire chemoresistance. Importantly, inhibition of LncRNA-HMG by anti-sense oligo (ASO) dramatically sensitizes CRC cells to chemotherapy in patient-derived xenograft (PDX) model. LncRNA-HMG is also a transcriptional target of β-catenin/TCF and activated Wnt signals trigger the marked upregulation of LncRNA-HMG. Collectively, these findings demonstrate that LncRNA-HMG promotes CRC chemoresistance and might be a prognostic or therapeutic target for CRC.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103362"},"PeriodicalIF":10.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003409/pdfft?md5=689cc7bfd95fbe1c8e45143778696b7b&pid=1-s2.0-S2213231724003409-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of NUDT16L1 sustains proper function of mitochondria and leads to ferroptosis insensitivity in colorectal cancer","authors":"Yi-Syuan Lin ,&nbsp;Ya-Chuan Tsai ,&nbsp;Chia-Jung Li ,&nbsp;Tzu-Tang Wei ,&nbsp;Jui-Lin Wang ,&nbsp;Bo-Wen Lin ,&nbsp;Ya-Na Wu ,&nbsp;Shang-Rung Wu ,&nbsp;Shin-Chih Lin ,&nbsp;Shih-Chieh Lin","doi":"10.1016/j.redox.2024.103358","DOIUrl":"10.1016/j.redox.2024.103358","url":null,"abstract":"<div><div>Cancer research is continuously exploring new avenues to improve treatments, and ferroptosis induction has emerged as a promising approach. However, the lack of comprehensive analysis of the ferroptosis sensitivity in different cancer types has limited its clinical application. Moreover, identifying the key regulator that influences the ferroptosis sensitivity during cancer progression remains a major challenge. In this study, we shed light on the role of ferroptosis in colorectal cancer and identified a novel ferroptosis repressor, NUDT16L1, that contributes to the ferroptosis insensitivity in this cancer type. Mechanistically, NUDT16L1 promotes ferroptosis insensitivity in colon cancer by enhancing the expression of key ferroptosis repressor and mitochondrial genes through direct binding to NAD-capped RNAs and the indirect action of MALAT1. Our findings also reveal that NUDT16L1 localizes to the mitochondria to maintain its proper function by preventing mitochondrial DNA leakage after treatment of ferroptosis inducer in colon cancer cells. Importantly, our orthotopic injection and Nudt16l1 transgenic mouse models of colon cancer demonstrated the critical role of NUDT16L1 in promoting tumor growth. Moreover, clinical specimens revealed that NUDT16L1 was overexpressed in colorectal cancer, indicating its potential as a therapeutic target. Finally, our study shows the therapeutic potential of a NUDT16L1 inhibitor in vitro, in vivo and ex vivo. Taken together, these findings provide new insights into the crucial role of NUDT16L1 in colorectal cancer and highlight its potential as a promising therapeutic target.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103358"},"PeriodicalIF":10.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003367/pdfft?md5=949fe321563227f06a5f54520d84902c&pid=1-s2.0-S2213231724003367-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142312626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensor systems of KEAP1 uniquely detecting oxidative and electrophilic stresses separately In vivo","authors":"Miu Sato ,&nbsp;Nahoko Yaguchi ,&nbsp;Takuya Iijima ,&nbsp;Aki Muramatsu ,&nbsp;Liam Baird ,&nbsp;Takafumi Suzuki ,&nbsp;Masayuki Yamamoto","doi":"10.1016/j.redox.2024.103355","DOIUrl":"10.1016/j.redox.2024.103355","url":null,"abstract":"<div><p>In the KEAP1-NRF2 stress response system, KEAP1 acts as a sensor for oxidative and electrophilic stresses through formation of S–S bond and C–S bond, respectively. Of the many questions left related to the sensor activity, following three appear important; whether these KEAP1 sensor systems are operating <em>in vivo</em>, whether oxidative and electrophilic stresses are sensed by the similar or distinct systems, and how KEAP1 equips highly sensitive mechanisms detecting oxidative and electrophilic stresses <em>in vivo</em>. To address these questions, we conducted a series of analyses utilizing KEAP1-cysteine substitution mutant mice, conditional <em>selenocysteine-tRNA</em> (<em>Trsp</em>) knockout mice, and human cohort whole genome sequence (WGS) data. Firstly, the <em>Trsp</em>-knockout provokes severe deficiency of selenoproteins and compensatory activation of NRF2. However, mice lacking homozygously a pair of critical oxidative stress sensor cysteine residues of KEAP1 fail to activate NRF2 in the <em>Trsp</em>-knockout livers. Secondly, this study provides evidence for the differential utilization of KEAP1 sensors for oxidative and electrophilic stresses <em>in vivo</em>. Thirdly, theoretical calculations show that the KEAP1 dimer equips quite sensitive sensor machinery in which modification of a single molecule of KEAP1 within the dimer is sufficient to affect the activity. WGS examinations of rare variants identified seven non-synonymous variants in the oxidative stress sensors in human KEAP1, while no variant was found in electrophilic sensor cysteine residues, supporting the fail-safe nature of the KEAP1 oxidative stress sensor activity. These results provide valuable information for our understanding how mammals respond to oxidative and electrophilic stresses efficiently.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103355"},"PeriodicalIF":10.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003331/pdfft?md5=9b6806c28b388417fc54d65d0c3f7862&pid=1-s2.0-S2213231724003331-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucoraphanin and sulforaphane mitigate TNFα-induced Caco-2 monolayers permeabilization and inflammation","authors":"Wei Zhu ,&nbsp;Eleonora Cremonini ,&nbsp;Angela Mastaloudis ,&nbsp;Patricia I. Oteiza","doi":"10.1016/j.redox.2024.103359","DOIUrl":"10.1016/j.redox.2024.103359","url":null,"abstract":"<div><p>Intestinal permeabilization is central to the pathophysiology of chronic gut inflammation. This study investigated the efficacy of glucoraphanin (GR), prevalent in cruciferous vegetables, particularly broccoli, and its derivative sulforaphane (SF), in inhibiting tumor necrosis factor alpha (TNFα)-induced Caco-2 cell monolayers inflammation and permeabilization through the regulation of redox-sensitive events. TNFα binding to its receptor led to a rapid increase in oxidant production and subsequent elevation in the mRNA levels of NOX1, NOX4, and Duox2. GR and SF dose-dependently mitigated both these short- and long-term alterations in redox homeostasis. Downstream, GR and SF inhibited the activation of the redox-sensitive signaling cascades NF-κB (p65 and IKK) and MAPK ERK1/2, which contribute to inflammation and barrier permeabilization. GR (1 μM) and SF (0.5–1 μM) prevented TNFα-induced monolayer permeabilization and the associated reduction in the levels of the tight junction (TJ) proteins occludin and ZO-1. Both GR and SF also mitigated TNFα-induced increased mRNA levels of the myosin light chain kinase, which promotes TJ opening. Molecular docking suggests that although GR is mostly not absorbed, it could interact with extracellular and membrane sites in NOX1. Inhibition of NOX1 activity by GR would mitigate TNFα receptor downstream signaling and associated events. These findings support the concept that not only SF, but also GR, could exert systemic health benefits by protecting the intestinal barrier against inflammation-induced permeabilization, in part by regulating redox-sensitive pathways. GR has heretofore not been viewed as a biologically active molecule, but rather, the benign precursor of highly active SF. The consumption of GR and/or SF-rich vegetables or supplements in the diet may offer a means to mitigate the detrimental consequences of intestinal permeabilization, not only in disease states but also in conditions characterized by chronic inflammation of dietary and lifestyle origin.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"76 ","pages":"Article 103359"},"PeriodicalIF":10.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003379/pdfft?md5=3818bf795240740f00a6be6aef1ddf29&pid=1-s2.0-S2213231724003379-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Withdrawal notice to: “Combinatorial lipidomics and proteomics underscore erythrocyte lipid membrane aberrations in the development of adverse cardio-cerebrovascular complications in maintenance hemodialysis patients” [Redox Biol. 76 (2024) 103295]","authors":"Ke Zheng ,&nbsp;Yujun Qian ,&nbsp;Haiyun Wang ,&nbsp;Dan Song ,&nbsp;Hui You ,&nbsp;Bo Hou ,&nbsp;Fei Han ,&nbsp;Yicheng Zhu ,&nbsp;Feng Feng ,&nbsp;Sin Man Lam ,&nbsp;Guanghou Shui ,&nbsp;Xuemei Li","doi":"10.1016/j.redox.2024.103356","DOIUrl":"10.1016/j.redox.2024.103356","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"76 ","pages":"Article 103356"},"PeriodicalIF":10.7,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142294100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired arterial dilation and increased NOX2 generated oxidative stress in subjects with ataxia-telangiectasia mutated (ATM) kinase","authors":"Lorenzo Loffredo ,&nbsp;Annarosa Soresina ,&nbsp;Bianca Laura Cinicola ,&nbsp;Martina Capponi ,&nbsp;Francesca Salvatori ,&nbsp;Simona Bartimoccia ,&nbsp;Vittorio Picchio ,&nbsp;Maurizio Forte ,&nbsp;Caterina Caputi ,&nbsp;Roberto Poscia ,&nbsp;Vincenzo Leuzzi ,&nbsp;Alberto Spalice ,&nbsp;Pasquale Pignatelli ,&nbsp;Raffaele Badolato ,&nbsp;Marzia Duse ,&nbsp;Francesco Violi ,&nbsp;Roberto Carnevale ,&nbsp;Anna Maria Zicari","doi":"10.1016/j.redox.2024.103347","DOIUrl":"10.1016/j.redox.2024.103347","url":null,"abstract":"<div><h3>Background</h3><div>Subjects with mutations in the Ataxia-Telangiectasia mutated (ATM) gene encoding for ATM kinase have a greater predisposition to develop atherosclerosis, but the mechanism behind this phenomenon is not yet understood. NADPH oxidase type 2 may play a role in this process, leading to endothelial dysfunction and an increased susceptibility to thrombosis. The purpose of this study was to assess the redox state in individuals with ATM mutations and determine its impact on endothelial function.</div></div><div><h3>Methods</h3><div>In this cross-sectional study, twenty-seven children with ataxia telangiectasia (AT) (13 males and 14 females, mean age 15.1 ± 7.6 years) were compared with 27 controls (13 males and 14 females, mean age 14.6 ± 8.4 years) matched for age and gender. Additionally, 29 AT parents with heterozygous mutation of ATM (h-ATM) gene, and 29 age- and gender-matched controls were included. Endothelial function was evaluated through brachial flow-mediated dilation (FMD) and the assessment of nitric oxide (NO) bioavailability. Oxidative stress was evaluated by measuring serum activity of soluble NOX2-dp (sNOX2-dp), hydrogen peroxide (H₂O₂) production, and hydrogen breakdown activity (HBA). Thrombus formation was assessed through the Total Thrombus Formation Analysis System (T-TAS).</div></div><div><h3>Results</h3><div>AT children and parents with heterozygous ATM mutations exhibited significantly lower FMD, HBA, and NO bioavailability as compared to age and gender matched controls. AT children and ATM carrier of heterozygous ATM mutations had significantly higher concentrations of sNOX2-dp and H₂O₂ as compared to controls. Compared to the respective controls, AT children and their parents, who carried heterozygous ATM mutation, showed an accelerated thrombus growth as revealed by reduced occlusion time. Multivariable linear regression analysis revealed that sNOX2 (standardized coefficient β: −0.296; SE: 0.044; p = 0.002) and NO bioavailability (standardized coefficient β: 0.224; SE: 0.065; p = 0.02) emerged as the only independent predictive variables associated with FMD (R²: 0.44).</div></div><div><h3>Conclusions</h3><div>This study demonstrates that individuals with ATM mutations experience endothelial dysfunction, increased oxidative stress, and elevated thrombus formation. These factors collectively contribute to the heightened susceptibility of these individuals to develop atherosclerosis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"77 ","pages":"Article 103347"},"PeriodicalIF":10.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARγ drives mitochondrial stress signaling and the loss of atrial cardiomyocytes in newborn mice exposed to hyperoxia","authors":"E. David Cohen ,&nbsp;Kyle Roethlin ,&nbsp;Min Yee ,&nbsp;Collynn F. Woeller ,&nbsp;Paul S. Brookes ,&nbsp;George A. Porter Jr. ,&nbsp;Michael A. O'Reilly","doi":"10.1016/j.redox.2024.103351","DOIUrl":"10.1016/j.redox.2024.103351","url":null,"abstract":"<div><p>Diastolic dysfunction is increasingly common in preterm infants exposed to supplemental oxygen (hyperoxia). Previous studies in neonatal mice showed hyperoxia suppresses fatty acid synthesis genes required for proliferation and survival of atrial cardiomyocytes. The loss of atrial cardiomyocytes creates a hypoplastic left atrium that inappropriately fills the left ventricle during diastole. Here, we show that hyperoxia stimulates adenosine monophosphate-activated kinase (AMPK) and peroxisome proliferator activated receptor-gamma (PPARγ) signaling in atrial cardiomyocytes. While both pathways can regulate lipid homeostasis, PPARγ was the primary pathway by which hyperoxia inhibits fatty acid gene expression and inhibits proliferation of mouse atrial HL-1 cells. It also enhanced the toxicity of hyperoxia by increasing expression of activating transcription factor (ATF) 5 and other mitochondrial stress response genes. Silencing PPARγ signaling restored proliferation and survival of HL-1 cells as well as atrial cardiomyocytes in neonatal mice exposed to hyperoxia. Our findings reveal PPARγ enhances the toxicity of hyperoxia on atrial cardiomyocytes, thus suggesting inhibitors of PPARγ signaling may prevent diastolic dysfunction in preterm infants.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"76 ","pages":"Article 103351"},"PeriodicalIF":10.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221323172400329X/pdfft?md5=25cda8a9cf5613da51752caefef98c1e&pid=1-s2.0-S221323172400329X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytic acid-loaded polyvinyl alcohol hydrogel promotes wound healing of injured corneal epithelium through inhibiting ferroptosis","authors":"Danni Gong ,&nbsp;Nianxuan Wu ,&nbsp;Huan Chen ,&nbsp;Weijie Zhang ,&nbsp;Chenxi Yan ,&nbsp;Chunlei Zhang ,&nbsp;Yao Fu ,&nbsp;Hao Sun","doi":"10.1016/j.redox.2024.103354","DOIUrl":"10.1016/j.redox.2024.103354","url":null,"abstract":"<div><p>As the important barrier of intraocular tissue, cornea is easy to suffer various kinds of injuries. Among them, acute alkali burn is a thorny ophthalmic emergency event, which can lead to corneal persistent epithelial defects, ulcers, and even perforation. Ferroptosis, a mode of regulatory cell death, has been found to play a key role in the process of corneal alkali burn, of which lipid peroxidation and intracellular iron levels are considered to be the possible therapeutic targets. To seek new effective treatments, the study herein focused on the occurrence of oxidative stress and ferroptosis in corneal alkali burn, exploring the role of phytic acid (PA), a natural small molecule with both antioxidant and iron chelating capacity, in the repair of corneal epithelial injury. The <em>in vivo</em> therapeutic results showed that PA eyedrops treatment promoted the recovery of corneal morphology and function, and <em>in vitro</em> experiments proved that PA prompted the repair of oxidative stress induced-corneal epithelial injury through ferroptosis inhibition. In addition, better drug treatment effect could be achieved through hydrogel delivery and sustained release, and our <em>in vivo</em> experiments showed the superior therapeutic effects of PA delivered by PVA hydrogels with larger molecular weights on corneal injury. In summary, this study demonstrated the excellent effect of natural small molecule PA with antioxidant and high efficiency chelating ferrous ions on ferroptosis inhibition, and showed the outstanding application prospect of PVA/PA hydrogels in the treatment of corneal epithelial injury.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"76 ","pages":"Article 103354"},"PeriodicalIF":10.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221323172400332X/pdfft?md5=83a4d7ec8c92cbc59725a032d471b7fa&pid=1-s2.0-S221323172400332X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142243772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors","authors":"Xuexia Xie ,&nbsp;Congcong Chen ,&nbsp;Cong Wang ,&nbsp;Yongjian Guo ,&nbsp;Binghe Sun ,&nbsp;Jiaxin Tian ,&nbsp;Jin Yan ,&nbsp;Dake Li ,&nbsp;Guo Chen","doi":"10.1016/j.redox.2024.103350","DOIUrl":"10.1016/j.redox.2024.103350","url":null,"abstract":"<div><p><em>BRCA1</em> is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.</p></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"76 ","pages":"Article 103350"},"PeriodicalIF":10.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213231724003288/pdfft?md5=fcaeb7e4336f550019c4bd1dc27c0c13&pid=1-s2.0-S2213231724003288-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142173228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}