Redox Biology最新文献

{"title":"Dimethyl malonate preserves brain and neurobehavioral phenotype following neonatal hypoxia–ischemia by inhibiting FTH1-mediated ferritinophagy","authors":"Yiming Jin , Xinxin Wang , Xiaowen Xu , Xiuwen Zhou , Qing Wang , Li Zhang , Lili Li , Meifang Jin , Hong Ni","doi":"10.1016/j.redox.2025.103792","DOIUrl":"10.1016/j.redox.2025.103792","url":null,"abstract":"<div><h3>Background</h3><div>Hypoxic–ischemic brain damage (HIBD) is a predominant cause of neuronal injury and mortality in newborns. Current preventive and therapeutic interventions demonstrate limited clinical efficacy. Emerging evidence reveals ferroptosis as a critical mechanism within HIBD pathophysiology, positioning it as a promising therapeutic target. Dimethyl malonate (DMM), a competitive inhibitor of succinate dehydrogenase, has demonstrated neuroprotective properties across multiple models of neurological disorders. However, the impact of DMM on the neonatal HIBD has not been studied.</div></div><div><h3>Aim</h3><div>To investigate the neuroprotective effects of DMM against neonatal HIBD and elucidate its mechanisms of action.</div></div><div><h3>Methods</h3><div>We created a model of HIBD in neonatal male C57BL/6J mice and administered various doses of DMM or vehicle control. Quantitative assessments included cerebral infarct volume measurement, Nissl staining for neurons, neurological behavior, ferrous ion (Fe<sup>2+</sup>), malondialdehyde (MDA) level, 4-hydroxynonenal (4-HNE) expression, and solute carrier family 7 member 11 (SLC7A11, system Xc<sup>−</sup>)/glutathione peroxidase 4 (GPX4) antioxidant axis expression level. Parallel studies in vitro employed oxygen-glucose deprivation/reperfusion-treated HT22 cells to investigate the effects of DMM on ferroptosis and its underlying mechanisms. Moreover, key factors of ferritinophagy, including nuclear receptor coactivator 4 (NCOA4), SQSTM1/p62, ferritin heavy chain 1 (FTH1), and microtubule-associated protein light 3 II (LC3II) were analyzed by western blotting. Molecular interactions between NCOA4 and FTH1 in brain cortical tissues of DMM-treated HIBD mice were analyzed by coimmunoprecipitation (Co-IP). Ferroptosis regulation by DMM was further investigated via <em>Fth1</em> knockdown in cellular models. Immunofluorescence staining was used to evaluate the capacity of DMM to suppress ferritin degradation and lysosomal Fe<sup>2+</sup> accumulation at the organelle level.</div></div><div><h3>Results</h3><div>DMM treatment demonstrated its neuroprotective efficacy in HIBD models, as evidenced by a reduction in cerebral infarct volume, an increase in the number of Nissl-positive neurons, and improved cognitive and motor functions in neonatal mice compared with controls. Additionally, the DMM intervention significantly modulated ferroptosis-related biomarkers in brain cortical tissues and HT22 cells, decreasing ferrous ion (Fe<sup>2+</sup>) accumulation, reducing lipid peroxidation products (MDA and 4-HNE), and enhancing SLC7A11/GPX4 antioxidant system activity. Importantly, DMM specifically regulated core ferritinophagy components: suppressing NCOA4 and LC3II expression while upregulating FTH1 and p62 levels. Co-IP revealed that mechanistically, DMM disrupted the protein interaction between NCOA4 and FTH1, effectively inhibiting ferritinophagy progression. The effects of antiferropto","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103792"},"PeriodicalIF":11.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144738358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF7IP inhibits Sorafenib-induced ferroptosis in hepatocellular carcinoma cells by inhibiting CYB5R2 transcription and stabilizing PARK7 protein","authors":"Yijie Su ,&nbsp;Sirui Huang ,&nbsp;Yang Duan ,&nbsp;Liang Zhang ,&nbsp;Shengyun Feng ,&nbsp;Yingge Lv ,&nbsp;Bei Lan ,&nbsp;Chenghao Xuan","doi":"10.1016/j.redox.2025.103786","DOIUrl":"10.1016/j.redox.2025.103786","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent form of programmed cell death, arises from the accumulation of lipid peroxides at toxic levels. Sorafenib, a first-line treatment for advanced hepatocellular carcinoma, shows limited clinical efficacy due to drug resistance. However, the mechanisms underlying Sorafenib resistance, especially related to ferroptosis, remain poorly understood. In this study, we identify activating transcription factor 7-interacting protein (ATF7IP) as a key inhibitor of ferroptosis. ATF7IP depletion promotes Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione (GSH) levels, increased lipid peroxidation, and altered mitochondrial crista structure. Notably, <em>ATF7IP</em> knockdown shows cooperative effects with Sorafenib in inhibiting hepatocellular carcinoma growth in mice. Mechanistically, ATF7IP interacts with SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to epigenetically silence the transcription of cytochrome <em>b</em>5 reductase 2 (CYB5R2), thereby reducing cellular Fe²⁺ levels. Meanwhile, ATF7IP stabilizes the antioxidant sensor Parkinsonism-associated deglycase (PARK7) protein which preserves the transsulfuration pathway to produce GSH, also leading to the inhibition of Sorafenib-induced ferroptosis. In conclusion, our findings identify ATF7IP as a critical ferroptosis inhibitor and represent ATF7IP as a novel therapeutic target for Sorafenib-based combination therapies of hepatocellular carcinoma.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103786"},"PeriodicalIF":10.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Parkinson's Disease: The interplay of cell death pathways, oxidative stress, and therapeutic innovations","authors":"Tingting Liu ,&nbsp;Xiangrui Kong ,&nbsp;Junbo Qiao ,&nbsp;Jianshe Wei","doi":"10.1016/j.redox.2025.103787","DOIUrl":"10.1016/j.redox.2025.103787","url":null,"abstract":"<div><div>Parkinson's disease (PD), a complex neurodegenerative disorder characterized by selective loss of substantia nigra (SN) dopaminergic neurons, pathological aggregation of α-synuclein (α-syn), and chronic neuroinflammation, is fundamentally driven by redox imbalance and oxidative stress. Recent studies reveal that a dynamic interplay of programmed and non-programmed cell death mechanisms—amplified by oxidative damage—drives PD progression. Programmed cell death pathways include apoptosis (caspase-dependent mitochondrial/extrinsic pathways), necroptosis (eceptor-interacting serine/threonine-protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL) axis), pyroptosis (NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome/Gasdermin D (GSDMD)-mediated pore formation), PARthanatos (DNA damage-poly ADP-ribose polymerase (PARP-1)/apoptosis-inducing factor (AIF) cascade), ferroptosis (redox imbalance-driven lipid peroxidation/glutathione peroxidase 4 (GPX4) inactivation), disulfidptosis (disulfide stress from cystine metabolic collapse), and cuproptosis (mitochondrial lipoylated protein toxicity via copper-mediated oxidative damage), while non-programmed necrosis is triggered by energy collapse and calcium overload. Mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and oxidative stress act as central redox hubs, integrating multiple death pathways through reactive oxygen species (ROS) bursts (O₂·^-, H₂O₂, ·OH), calcium dysregulation, and metabolic abnormalities, forming a self-amplifying vicious cycle. Non-neuronal cells (e.g., microglia and astrocytes) exacerbate neuronal redox damage by releasing pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)), dysregulating iron/copper metabolism (enhancing Fenton chemistry), and suppressing autophagic flux. Therapeutic strategies targeting redox-critical nodes include caspase/RIPK1 inhibition, GPX4 activators, autophagy modulators (rapamycin), acid β-glucocerebrosidase (GBA1) restoration, iron/copper chelators, and antioxidants (N-acetylcysteine) to restore glutathione homeostasis. Additionally, regulating glial polarization (triggering receptor expressed on myeloid cells 2 (TREM2) agonists) may disrupt inflammation-redox-death loops. Future challenges include deciphering spatiotemporal heterogeneity of cell death, developing multi-target redox therapies, and advancing biomarker-driven precision medicine (circulating free DNA (cfDNA), <em>p</em>-MLKL). Targeting redox dysregulation will guide breakthrough PD therapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103787"},"PeriodicalIF":10.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144702215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a BACH1 lung cancer signature: A novel tool for understanding BACH1 biology and identifying new inhibitors","authors":"Donika Klenja-Skudrinja ,&nbsp;Kevin X. Ali ,&nbsp;David Walker ,&nbsp;Maureen Higgins ,&nbsp;Angana AH. Patel ,&nbsp;Dorota Raj ,&nbsp;Anna Creelman ,&nbsp;Charlotte McDowall ,&nbsp;Conor Taylor ,&nbsp;Tomasz Wenta ,&nbsp;Erik Larsson ,&nbsp;Clotilde Wiel ,&nbsp;Volkan I. Sayin ,&nbsp;Laureano de la Vega","doi":"10.1016/j.redox.2025.103789","DOIUrl":"10.1016/j.redox.2025.103789","url":null,"abstract":"<div><div>BACH1 is a transcriptional repressor that regulates oxidative stress and inflammatory responses and has emerged as a promising therapeutic target in cancer and other diseases. In lung cancer, BACH1 overexpression is linked to poor prognosis and metastasis, yet a consistent transcriptional signature reflecting its activity has not yet been defined. To address this, we performed RNA-Seq coupled with ChIP-Seq in BACH1-proficient and BACH1-deficient lung cancer cells, identifying a set of direct BACH1 target genes. This novel lung cancer BACH1 signature is highly sensitive and specific to BACH1 perturbation, unaffected by NRF2 modulation, and consistent across a large panel of cancer cell lines. Despite NRF2 binding to the same regions, BACH1-mediated gene repression is dominant over NRF2-driven gene activation, suggesting a previously unappreciated regulatory hierarchy between these two transcription factors. Importantly, this signature correlates with BACH1 basal levels in lung cancer, PDAC and melanoma cells, highlighting its relevance as a surrogate for BACH1 activity. Using this signature, we identified paeoniflorin as a novel FBXO22-dependent BACH1 degrader with anti-invasive activity, and the novel BACH1 target gene HTRA3 as a potential effector of BACH1's pro-migratory effect.</div><div>In summary, this novel BACH1 signature holds potential as a therapeutically relevant biomarker for identifying lung tumours with elevated BACH1 activity, serves as a powerful platform for discovering anti-invasive BACH1 inhibitors, and provides mechanistic insights into BACH1's role in driving metastasis.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103789"},"PeriodicalIF":10.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fusion of a bacterial cysteine desulfurase to redox-sensitive green fluorescent protein produces a highly sensitive cysteine biosensor for monitoring changes in intracellular cysteine","authors":"Damien Caubrière ,&nbsp;Arthur de Butler ,&nbsp;Anna Moseler ,&nbsp;Pauline Leverrier ,&nbsp;Jean-François Collet ,&nbsp;Andreas J. Meyer ,&nbsp;Nicolas Rouhier ,&nbsp;Jérémy Couturier","doi":"10.1016/j.redox.2025.103785","DOIUrl":"10.1016/j.redox.2025.103785","url":null,"abstract":"<div><div>Over the last two decades, the development of fluorescent probes has transformed the way of measuring physiological parameters in intact cells, including in the field of redox biology. We developed a genetically encoded biosensor called CyReB to monitor intracellular cysteine in real time. This biosensor exploits the ability of a particular bacterial cysteine desulfurase to promote the oxidation of reduction-oxidation-sensitive green fluorescent protein 2 in the presence of cysteine. The specificity, sensitivity, and the oxidation-reduction dynamics of CyReB were first investigated <em>in vitro</em> before its <em>in vivo</em> functionality was confirmed by expressing CyReB in <em>Escherichia coli</em> and <em>Saccharomyces cerevisiae</em> cells. Expressing CyReB or an inactive version in wild-type and various mutant strains of <em>Escherichia coli</em> showed that this sensor could be used to monitor intracellular cysteine dynamics, particularly in the context of the cysteine-cystine shuttle system. This work demonstrates how using this cysteine biosensor should provide new insights into the metabolism of cysteine and cysteine-related pathways in various model organisms.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103785"},"PeriodicalIF":10.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144712968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target","authors":"Jinghao Cao ,&nbsp;Xi Chen ,&nbsp;Lulu Chen ,&nbsp;Yajuan Lu ,&nbsp;Yunyi Wu ,&nbsp;Aoli Deng ,&nbsp;Feifan Pan ,&nbsp;Hangqi Huang ,&nbsp;Yingchao Liu ,&nbsp;Yanchun Li ,&nbsp;Xiangmin Tong ,&nbsp;Jing Du","doi":"10.1016/j.redox.2025.103788","DOIUrl":"10.1016/j.redox.2025.103788","url":null,"abstract":"<div><div>Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms underlying ferroptosis involve a complex interplay of multiple subcellular organelles, orchestrating iron homeostasis, lipid metabolism, and the generation of reactive oxygen species (ROS) that drive peroxidation processes, ultimately leading to membrane damage and cell death. Numerous antioxidant systems play pivotal roles in regulating and preventing ferroptosis, among which the recently identified mitochondrial inner membrane enzyme dihydroorotate dehydrogenase (DHODH) represents a novel therapeutic target for ferroptosis intervention. This systematic review comprehensively elucidates several key cellular defense mechanisms against ferroptosis that counteract ROS-driven peroxidation and operate through distinct subcellular localizations. We particularly focus on delineating the molecular mechanisms by which DHODH regulates ferroptosis, with special emphasis on its role in suppressing mitochondrial lipid peroxidation. Furthermore, we systematically evaluate the therapeutic potential of DHODH inhibitors in oncology, virology, and immune-inflammatory disorders. By integrating ferroptosis biology with DHODH-mediated cytoprotective networks, this review aims to provide mechanistic insights and novel therapeutic strategies for cancer and oxidative stress-related disorders.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103788"},"PeriodicalIF":10.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PNKP targeting engages the autophagic machinery through STING and STAT3 to potentiate ferroptosis and chemotherapy in TNBC","authors":"Avi Maimon ,&nbsp;Pier Giorgio Puzzovio ,&nbsp;Yaron Vinik ,&nbsp;Gavriel-David Hannuna ,&nbsp;Sara Donzelli ,&nbsp;Daniela Rutigliano ,&nbsp;Giovanni Blandino ,&nbsp;Sima Lev","doi":"10.1016/j.redox.2025.103775","DOIUrl":"10.1016/j.redox.2025.103775","url":null,"abstract":"<div><div>The polynucleotide kinase/phosphatase (PNKP) is a DNA repair enzyme possessing bifunctional DNA 3′-phosphatase and DNA 5′-kinase activities. It plays an important role in the rejoining of single- and double-strand DNA breaks and is considered as a potential therapeutic target for different cancer types. Here we show that PNKP is highly expressed in triple negative breast cancer (TNBC) and associated with poor prognosis and chemoresistance. Targeting of PNKP enhanced ferroptosis in TNBC, which was associated with increased labile iron pool and ROS and concomitantly decreased in intracellular glutathione, SCD1 and GPX4 levels. Transcriptomic profiling and mechanistic data indicate that PNKP targeting robustly enhances the lysosomal and the autophagic machinery by activating STING and concurrently inhibiting STAT3, thereby increasing ferritinophagy, intracellular iron level and modulating the expression of key ferroptosis regulators. Importantly, PNKP and STAT3 are rapidly phosphorylated, colocalize, and interact upon ferroptosis induction or doxorubicin treatment, the first line treatment for TNBC patients. Targeting PNKP together with doxorubicin synergistically inhibited the growth of TNBC in an animal model and of TNBC-patients derived organoids. These results offer a promising therapeutic combination for TNBC and highlight the clinical potential of PNKP targeting and ferroptotic death for TNBC therapy.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"86 ","pages":"Article 103775"},"PeriodicalIF":11.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144738285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in KEAP1-based PROTACs as emerging therapeutic modalities: Structural basis and progress","authors":"Jing Chen ,&nbsp;Disheng Feng ,&nbsp;Rui Zhu ,&nbsp;Hua Li ,&nbsp;Lixia Chen","doi":"10.1016/j.redox.2025.103781","DOIUrl":"10.1016/j.redox.2025.103781","url":null,"abstract":"<div><div>Kelch-like ECH-associated protein 1 (KEAP1) functions as a substrate adaptor for the Cullin 3-RING E3 ligase complex, mediating the ubiquitination and subsequent proteasomal degradation of nuclear factor erythroid 2-related factor 2 (NRF2). This regulatory mechanism maintains cellular redox homeostasis by preventing NRF2 overactivation. Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic strategy that harnesses the ubiquitin-proteasome system for targeted protein degradation. Recent advancements have expanded the repertoire of E3 ligases exploitable for PROTAC design, with KEAP1 identified as a promising candidate. This review provides a comprehensive overview of the structural and functional characteristics of KEAP1, detailing its interactions with NRF2 and Cullin 3. The development of KEAP1- recruiting PROTACs utilizing ligands derived from different classes of known KEAP1 inhibitors—including short peptides, covalent small molecules (e.g., CDDO derivatives), and non-covalent inhibitors (e.g., KI696)—is discussed, highlighting the potential to diversify the available E3 ligase recruiters. Recent progress in developing KEAP1-based PROTACs targeting BRD4, CDK9, FAK, Tau and KEAP1 itself is highlighted, with particular emphasis on ligand optimization strategies employed to enhance degradation efficacy and specificity. Elucidating the structural basis of KEAP1 interactions provides crucial insights for advancing PROTAC applications. However, current challenges in KEAP1-based targeted protein degradation warrant further investigation to fully realize its therapeutic potential. Future research should focus on optimizing KEAP1 ligand properties and exploring novel protein targets amenable to degradation via KEAP1 recruitment to further advance this innovative therapeutic modality.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103781"},"PeriodicalIF":10.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144702216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effect of hydroxytyrosol against hyperglycemia-induced phosphatidylserine exposure in human erythrocytes: focus on dysregulation of calcium homeostasis and redox balance","authors":"Rosaria Notariale ,&nbsp;Claudia Moriello ,&nbsp;Nicola Alessio ,&nbsp;Vitale Del Vecchio ,&nbsp;Luigi Mele ,&nbsp;Pasquale Perrone ,&nbsp;Caterina Manna","doi":"10.1016/j.redox.2025.103783","DOIUrl":"10.1016/j.redox.2025.103783","url":null,"abstract":"<div><div>Diabetes is a widespread chronic disease that poses serious health concerns due to its numerous associated complications, including an increased risk of cardiovascular diseases. Under conditions of prolonged hyperglycemia, erythrocytes (RBC) undergo the breakdown of the natural phospholipid asymmetry, triggered by cell surface exposure of phosphatidylserine (PS) associated with increased prothrombotic activity. The aim of the present study was to provide insights into the potential molecular mechanisms underlying, focusing on two phospholipid translocases, ATP-dependent flippase ATP11C and calcium-dependent scramblase PLSCR1. The possible protective effect exerted by the hydroxytyrosol (HT), a powerful phenolic antioxidant present in olive oil, was also tested. Exposure of intact human RBC to high glucose (25–50 mM) results in a dose-dependent increase in PS-exposing RBC, which can be prevented by HT at concentrations as low as 5 μM. Furthermore, our study reveals that PLSCR1 activity is significantly higher under hyperglycemic conditions. In line with this finding, immunocytochemical analysis indicates increased membrane expression of this enzyme. Both alterations can be prevented by HT pre-treatment. Conversely, no variation in ATP11C is observable. Importantly, intracellular calcium measurement reveals a significant rise, suggesting that dysregulation of calcium homeostasis may be a key mechanism underlying both the change in scramblase activity as well as the HT protective effect observed. In this case too, in fact, HT exhibits a protective effect. Accordingly, when cells are exposed to high glucose in a calcium-free medium no variation is observable. Finally, we report that HT is able to prevent glucose-induced alteration in redox balance by reducing ROS formation and the decline in intracellular glutathione, likely due to its high scavenging potential as well as to the proposed recycling process cycle that could regenerate reduced glutathione from its radical. All together our findings point to RBC as an additional target in the management of the cardiovascular complications associated with diabetes and indicate HT as nutritional/nutraceutical strategy for their prevention in diabetic patients.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103783"},"PeriodicalIF":10.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of NRF2 and AMPK signaling in aging and progeria: a digest","authors":"Eleni Petsouki ,&nbsp;Vasileios Gerakopoulos ,&nbsp;Despoina D. Gianniou ,&nbsp;Elke H. Heiss ,&nbsp;Ioannis P. Trougakos","doi":"10.1016/j.redox.2025.103782","DOIUrl":"10.1016/j.redox.2025.103782","url":null,"abstract":"<div><div>Aging refers to a <em>gradual, continuous process of natural change</em> which is accompanied by progressive loss in physiological functions and an increased risk of frailty, disease, and death. Cells face a declining capacity to adapt homeostasis after perturbation, resulting among others in an imbalance in reactive species production and damage removal, as well as in energy or nutrient sensing and usage. NRF2 (Nuclear factor E2 p45‐related factor 2) is a transcription factor primarily known to regulate the expression of genes involved in cellular defense against oxidative, proteotoxic, or xenobiotic stress. AMPK (AMP-activated protein kinase), a serine/threonine kinase, serves as a central sensor of cellular energy status, maintaining ATP levels by tweaking the ratio of anabolic and catabolic pathways. Cooperativity between AMPK and NRF2 signaling, which goes beyond mere parallel activation in situations of cellular stress, has been previously described. This narrative short review zooms in the current understanding of NRF2 and AMPK signaling, alone or in concert, in aging and Hutchinson–Gilford Progeria Syndrome (HGPS), a genetic disorder characterized by premature aging.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103782"},"PeriodicalIF":10.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}