Redox Biology最新文献

{"title":"Supplement-driven iron overload accelerates phenotypic aging via inflammatory biomarkers: Potential counteraction through anti-inflammatory or antioxidant diets","authors":"Bin Li ,&nbsp;Zhu Ming ,&nbsp;Yina Wang ,&nbsp;Yingfeng Zhang ,&nbsp;Runyi Zhou ,&nbsp;Can Zhang ,&nbsp;Yue Wu ,&nbsp;Guoliang Wang ,&nbsp;Hongquan Xie ,&nbsp;Ying Li ,&nbsp;Ran Li","doi":"10.1016/j.redox.2025.103733","DOIUrl":"10.1016/j.redox.2025.103733","url":null,"abstract":"<div><div>Given the dual effects of iron on health, we carried out this study to explore its relationship with phenotypic age (PhenoAge) and to evaluate the roles of inflammation and oxidative stress in this regard. Since these associations are still poorly understood, elucidating them is vital for understanding aging-related health outcomes. A cross-sectional study was conducted using NHANES 2017–2018 data, involving 8692 participants aged 20 years or older. The nonlinear relationships between iron intake and PhenoAge acceleration (PhenoAgeAccel) were assessed using weighted restricted cubic splines (RCS). Multivariable-adjusted analyses were performed using weighted generalized linear models (GLMs). K-means clustering was employed to identify patterns of iron co-exposure. Interaction effects were assessed using likelihood ratio tests, while mediation analyses were conducted to quantify the contributions of inflammation and oxidative stress markers. This study identified a U-shaped relationship between total iron intake and PhenoAgeAccel (breakpoint: 18.441 mg/day). Below this threshold, higher iron intake was protective against aging (β = −0.126); above it, aging accelerated (β = 0.021). Notably, dietary iron derived solely from food was not associated with any harmful effects on aging. In contrast, supplemental iron intake showed a positive association with PhenoAgeAccel (β = 0.017), highlighting the potential risks of excessive supplement use. Moreover, the aforementioned associations showed no gender differences. Cluster analysis split participants into two groups: dietary iron reference (DIR), mostly below the UL (45 mg/day) with minimal supplemental iron; and supplement-driven iron overload (SDIO), all exceeding the UL, with supplemental iron comprising 83.44 % of total intake on average. SDIO showed significantly faster phenotypic aging (β = 1.774) than DIR. However, anti-inflammatory or antioxidant diets were able to counteract this detrimental effect (<em>P</em> for interaction = 0.025). Inflammation-related markers partially mediated SDIO-associated aging acceleration (mediation proportion: 15.53 %–25.63 %). The results stayed robust even after adjusting for variables related to anemia and post-menstrual status. This study suggests that excessive use of supplements, resulting in iron overload, may accelerate individual aging through inflammation-related pathways. Nevertheless, a diet abundant in anti-inflammatory or antioxidant properties could counteract this heightened risk of aging.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103733"},"PeriodicalIF":10.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337670","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":"Endothelial soluble epoxide hydrolase links polyunsaturated fatty acid metabolism to oxidative stress and atherosclerosis progression","authors":"Minghua Cao ,&nbsp;Mengqing Li ,&nbsp;Xixuan Li ,&nbsp;Yuanyuan Li ,&nbsp;Yunyun Chen ,&nbsp;Maria-Kyriaki Drekolia ,&nbsp;Xiang Cheng ,&nbsp;Fredy Delgado Lagos ,&nbsp;Sofia-Iris Bibli ,&nbsp;Jiong Hu","doi":"10.1016/j.redox.2025.103730","DOIUrl":"10.1016/j.redox.2025.103730","url":null,"abstract":"<div><div>Atheroslcerosis manifests as localized lesions within the vascular tree, preferentially affecting arteries at branch points, the outer wall of bifurcations and the inner walls of curvatures. Such spatial localized sensitivity to atherosclerosis, can be partially attributed to endothelial cell heterogeneity which compromises vascular fitness and contributes to the pathogenesis of the diseases. Here we identified that in a subcluster of aortic endothelial cells characterized with atheroprone gene signatures, the polyunsaturated fatty acids (PUFAs) metabolic enzyme soluble epoxide hydrolase (sEH) is selectively upregulated. Genetic endothelial-specific overexpression of the sEH resulted in excessive and accelerated atherosclerosis development, while inducible endothelial-specific deletion of sEH protected against PCSK9 mediated atherosclerotic plaque formation. Mechanistically, sEH-derived docosahexaenoic acid (DHA) diol (19,20-DHDP) disrupts mitochondrial protein-cholesterol associations in endothelial cells, which through reduced oxidizing metabolic import of pyruvate and malate inhibited mitochondrial Complex I activity. Such inhibition, resulted in a lowering of the mitochondrial membrane potential and subsequent excessive mitochondrial reactive oxygen species production and disrupted mitochondrial structure. Heightened mitochondrial redox generation ultimately led to TGFβ activation and the subsequent stimulation of an athroprone and pro-inflammatory endothelial transcriptional programme. Re-establishing redox homeostasis by antioxidant treatments, halted the atheroprone phenotypes of sEH overexpressing vessels. Our data propose that manipulating endothelial PUFA metabolism and sEH activity in the endothelium can exert vascular protective effects.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103730"},"PeriodicalIF":10.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304882","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":"Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans","authors":"Steffi M. Jonk ,&nbsp;Alan Nicol ,&nbsp;Vicki Chrysostomou ,&nbsp;Emma Lardner ,&nbsp;Shu-Che Yu ,&nbsp;Gustav Stålhammar ,&nbsp;Jonathan G. Crowston ,&nbsp;James R. Tribble ,&nbsp;Peter Swoboda ,&nbsp;Pete A. Williams","doi":"10.1016/j.redox.2025.103732","DOIUrl":"10.1016/j.redox.2025.103732","url":null,"abstract":"<div><div>Sarcopenia is the age-related degeneration of skeletal muscle, resulting in loss of skeletal muscle tone, mass, and quality. Skeletal muscle is a source of systemic metabolites and macromolecules important for neuronal health, function, and healthy neuronal aging. Age-related loss of skeletal muscle might result in decreased metabolite and macromolecule availability, resulting in reduced neuronal function or increased susceptibility to unhealthy aging and neurodegenerative diseases. We aimed to identify muscle metabolite candidates that regulate healthy aging. C57BL/6J mice were aged to young adult (4 months) and old age (25 months) and skeletal muscle was collected. Age-related muscle loss was confirmed by reduced muscle mass, muscle fiber degeneration, reduced myosin intensity, in addition to a metabolic shift and increased DNA damage in skeletal muscle. Using a low molecular weight enriched metabolomics protocol, we assessed the metabolic profile of skeletal muscle from young adult and old age mice and identified 20 metabolites that were significantly changed in aged muscle. These metabolite candidates were tested in <em>C. elegans</em> assays of lifespan, healthspan, muscle, and mitochondrial morphology under normal and stressed conditions. We identified four metabolite candidates (beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, pantothenic acid) that, when supplemented in <em>C. elegans</em> provided robust gero- and mitochondrial protection. These candidates also affected life-, and health- span in <em>C. elegans</em> models of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Our findings support that aging muscle can be used to identify novel metabolite modulators of lifespan and health and may show promise for future treatments of neurodegenerative and neuromuscular disorders.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103732"},"PeriodicalIF":10.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304856","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":"Corrigendum to \"Nitro-Oleic acid protects from neovascularization, oxidative stress, gliosis and neurodegeneration in oxygen-induced retinopathy\" [Redox Biol. 83 (2025) 103634].","authors":"María Victoria Vaglienti, María Constanza Paz, María Victoria Gutierrez, Paula Virginia Subirada, Jose Luna, Gustavo Bonacci, María Cecilia Sánchez","doi":"10.1016/j.redox.2025.103725","DOIUrl":"https://doi.org/10.1016/j.redox.2025.103725","url":null,"abstract":"","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":" ","pages":"103725"},"PeriodicalIF":10.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294848","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":"Caged-hypocrellin mediated photodynamic therapy induces chromatin remodeling and disrupts mitochondrial energy metabolism in multidrug-resistant Candida auris","authors":"Xinyao Liu ,&nbsp;Yiran Tao ,&nbsp;Linwan Zhang ,&nbsp;Yuzhou Liu ,&nbsp;Dongmei Shi ,&nbsp;Jiao Wang ,&nbsp;Peng Xue ,&nbsp;Bin Xu ,&nbsp;Wenjie Fang ,&nbsp;Yuping Ran","doi":"10.1016/j.redox.2025.103708","DOIUrl":"10.1016/j.redox.2025.103708","url":null,"abstract":"<div><div><em>Candida auris</em> is a fungal pathogen with frequent development of multidrug-resistance or pan-drug resistance. Currently, the treatment options for <em>Candida auris</em> are limited. Therefore, there is an urgent need for alternative therapeutic strategies. Antimicrobial photodynamic therapy (aPDT), which generates reactive oxygen species (ROS) through light-activated photosensitizers, has shown promise against <em>C. auris</em>; however, its molecular mechanism remains unclear. To investigate COP1T-HA-mediated PDT-induced genomic alterations, we constructed a 3D genome map of <em>Candida</em> species, which uncovered the reorganization of chromatin architecture in response to PDT treatment. Our data showed that low-dose PDT causes subtle local adjustments in chromatin topology, whereas high-dose PDT leads to more pronounced changes in A/B compartmentalization, topologically associating domain (TAD) organization, and chromatin looping associated with key genes related to mitochondrial energy metabolism. Confocal imaging confirmed that high-dose <strong>COP1T-HA-mediated PDT</strong> induces localized ROS accumulation near the nucleus and a temporally ordered cellular stress response. Furthermore, functional validation through <em>QCR10</em>, <em>NDUFA5</em>, and <em>MP</em> knockouts confirmed the essential roles of these genes in mitochondrial integrity, ATP synthesis, ROS homeostasis, and biofilm formation. Mutants showed altered mitochondrial membrane potential, intracellular pH imbalance, and enhanced glycolytic compensation, highlighting the impact of electron transport disruption on energy metabolism. This study provides the first comprehensive insight into <strong>COP1T-HA-mediated</strong> PDT-induced chromatin reorganization in <em>C. auris</em> and establishes a direct connection between 3D genome remodeling and fungal energy metabolism, offering a foundation for chromatin-targeted antifungal strategies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103708"},"PeriodicalIF":10.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304858","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":"3-O-trans-p-coumaroyl esterification enhances the anti-inflammatory effects of tormentic acid by targeting NF-κB signaling","authors":"Mara Heckmann ,&nbsp;Lea Karlsberger ,&nbsp;Bernhard Blank-Landeshammer ,&nbsp;Gerald Klanert ,&nbsp;Nadiia Sadova ,&nbsp;Verena Stadlbauer ,&nbsp;Georg Sandner ,&nbsp;Theresa Gramatte ,&nbsp;Simone Kasis ,&nbsp;Julian Weghuber","doi":"10.1016/j.redox.2025.103731","DOIUrl":"10.1016/j.redox.2025.103731","url":null,"abstract":"<div><div>Tormentic acid (TA), a plant-derived pentacyclic triterpene, exhibits antioxidant and anti-inflammatory potential, yet the pharmacological effects of its 3-<em>O</em>-trans-<em>p</em>-coumaroyl ester (<em>trans</em>-TACE) remain underexplored. This study investigates how hydroxycinnamoyl esterification influences the biological activity of pentacyclic triterpenes by comparing TA and <em>trans</em>-TACE in cellular and <em>in vivo</em> stress models.</div><div>We assessed their ability to mitigate oxidative stress by evaluating the inhibition of ROS and NO molecules. Pro-inflammatory cytokine production in LPS-stimulated THP-1 macrophages was analyzed through cytokine arrays and multiplex immunoassays, while NF-κB activation was examined in both TLR4-dependent and -independent models using HEK-Blue reporter cells. Uptake efficiencies into Caco-2 enterocytes were measured via LC-MS. The <em>in vivo</em> relevance of these findings was assessed using <em>C. elegans</em> as a model for oxidative and inflammatory stress response.</div><div>Results showed that <em>trans</em>-TACE significantly reduced cellular ROS and NO levels compared to TA. Protein analyses of LPS-stimulated THP-1 macrophages indicated that <em>trans</em>-TACE significantly decreased pro-inflammatory cytokines involved in NF-κB signaling (<em>e.g</em>., TNFα, IL-8, CCL2, CXCL5 and CXCL11). <em>Trans</em>-TACE also inhibited NF-κB activation in both TLR4-dependent and -independent models. In <em>C. elegans</em>, both TA and <em>trans</em>-TACE downregulated several stress-induced genes, with <em>trans</em>-TACE exhibiting broader effects by additionally targeting <em>daf-16</em> and <em>gst-4</em> gene expression. Moreover, we revealed key differences in bioactivities between the trans and cis isoform of TACE, underscoring the importance of considering the structural properties of geometric isomers in therapeutic assessments.</div><div>Overall, this study suggests that esterification significantly enhances the biological activity of pentacyclic triterpenes and points towards new possibilities for developing effective natural anti-inflammatory therapies.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103731"},"PeriodicalIF":10.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290970","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":"High-dose vitamin C as a targeted treatment for KRAS-driven cancers?","authors":"Elisabeth Mack ,&nbsp;Christian Rau ,&nbsp;Cornelia Otet ,&nbsp;Jonas Aaron Schäfer ,&nbsp;Cornelia Brendel ,&nbsp;Albert Grass ,&nbsp;Peer Bredow ,&nbsp;Christian Hohl ,&nbsp;Carsten Denkert ,&nbsp;Frank Willeke ,&nbsp;Andreas Neubauer","doi":"10.1016/j.redox.2025.103726","DOIUrl":"10.1016/j.redox.2025.103726","url":null,"abstract":"<div><div>KRAS mutations are frequently observed in human cancer and are associated with proliferation, therapy-resistance and worse outcome. Regrettably, only a fraction of possible mutations is druggable. Therefore, a tailored and possibly cost-effective method to overcome this issue is urgently needed.</div><div>Recently, Bodeker et al. presented a randomized phase II trial investigating whether high-dose vitamin C (ascorbate) improved overall survival in metastatic pancreatic cancer (Bodeker et al., Redox Biol 2024). This may be due to the high frequency of KRAS mutations in pancreatic cancer (&gt;90 %), as, in the case of oncogenic RAS, high-dose vitamin C becomes synthetic lethal when added to chemotherapy, as previously shown by the work of Cantley and coworkers (Yun et al., Science, 2015)</div><div>It is unclear, however, if this observation holds true also for rare KRAS mutations. Recently we treated a 43 year old male patient with metastatic duodenal cancer and an atypical KRAS mutation A59T using FOLFOX-chemotherapy with high-dose vitamin C as second line therapy. The tumor had progressed after first line immune checkpoint therapy as the tumor presented with microsatellite instability. Restaging after 8 cycles of FOLFOX + high-dose vitamin C therapy revealed regression of the tumor mass and extensive tumor necrosis. Thus, our personalized experimental approach yielded in a greater clinical benefit for the patient than the previous standard therapy, particularly a PFS-2/PFS-1 ratio of &gt;2.</div><div>Obviously we do not know whether this response could have also been observed if chemotherapy was given w/o high-dose vitamin C. As up to now two randomized clinical trials showed a beneficial effect of the addition of high-dose vitamin C (pancreatic cancer: Bodeker et al., colorectal cancer: Vitality trial), and, in the case of Vitality, the benefit was restricted to KRAS mutated tumors only, more clinical trials addressing this topic are needed. Therefore, we thank Bodeker et al. for contributing these important data.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103726"},"PeriodicalIF":10.7,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304857","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":"Novel and superior treatment of pulmonary hypertension with netrin-1 derived, modified and improved small peptides","authors":"Priya Murugesan,&nbsp;Yuhan Zhang,&nbsp;Yixuan Zhang,&nbsp;Ji Youn Youn,&nbsp;Hua Cai","doi":"10.1016/j.redox.2025.103710","DOIUrl":"10.1016/j.redox.2025.103710","url":null,"abstract":"<div><div>Pulmonary hypertension (PH) is a severe and lethal cardiorespiratory disorder with limited therapeutic options to effectively stop or regress the development of the disease. We have previously demonstrated that netrin-1 protects against cardiac injuries via modest and stable production of nitric oxide (NO) and attenuation of oxidative stress. In view of the intermediate roles of NO deficiency and oxidative stress in the pathogenesis of PH, we have recently shown novel and potent attenuating effects on PH of netrin-1 and netrin-1 derived small peptides. Currently, we investigated therapeutic effects on PH of netrin-1 derived peptides with modifications to increase their stability, permeability and resistance to oxidative stress, which are anticipated to have improved efficacies in alleviating PH. Indeed, modified peptides of V1P, V2P, V3P, V1S, V1T, V1D, V1C turned out to be superior or more robust in alleviating all of the pathophysiological and molecular features of PH in hypoxia exposed mice either substantially or completely, with peptides V1S and V1C attenuating both mPAP and RVSP to below baseline levels. All modified peptides completely attenuated right heart hypertrophy more effectively than netrin-1 and the original peptides. They were also more effective in abrogating characteristic vascular remodeling (medial thickening, muscularization, increases in cell proliferation and fibrosis), and production of total ROS and mitochondrial superoxide. eNOS uncoupling activity was abolished by the modified peptides, which was accompanied by restoration in NO bioavailability. Taken together, these novel findings demonstrate that modified, netrin-1 derived small peptides are superior in treating PH, with improved or more robust effects in attenuating all of the mechanistic pathways and hallmark phenotypes of PH. Since these modified peptides pocess properties being more easily deliverable with enhanced stability and availability, they might be more readily translatable to clinical practice for the treatment of PH for which new therapeutics are urgently in need.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103710"},"PeriodicalIF":10.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304859","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":"Fructose intake enhances lipoteichoic acid-mediated immune response in monocytes of healthy humans","authors":"Raphaela Staltner,&nbsp;Katja Csarmann,&nbsp;Amelie Geyer,&nbsp;Anika Nier,&nbsp;Anja Baumann,&nbsp;Ina Bergheim","doi":"10.1016/j.redox.2025.103729","DOIUrl":"10.1016/j.redox.2025.103729","url":null,"abstract":"<div><div>Metabolic diseases like type 2 diabetes are afflicted with higher rates of infections and longer, more complicated infection course as well as higher fatality rates. The impact of nutrition and specific nutrients like free fructose herein has not yet been fully understood. Here, we performed dietary intervention studies in healthy individuals and performed <em>ex vivo</em> experiments in isolated blood immune cells to assess the effects of dietary fructose intake on Gram-positive bacterial toxin induced immune responses. Acute and extended intake of fructose but not glucose was related with an induction of <em>Toll like receptor</em> 2 mRNA expression in monocytes and enhanced the LTA-dependent release of proinflammatory cytokines from monocytes. Blocking fructose metabolism and transcription factor SP1 attenuated the fructose-related induction of <em>Toll like receptor</em> 2 mRNA expression and augmentation of proinflammatory cytokine release further suggesting that fructose-dependent metabolic alterations are critical in enhancing immune responsiveness of humans after fructose consumption.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103729"},"PeriodicalIF":10.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279209","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":"Revised model for cell cycle regulation by iron: differential roles between transferrin and ferritin","authors":"Ryo Yanagiya ,&nbsp;Hiroko Kato ,&nbsp;Akinori Ninomiya ,&nbsp;Masaya Ueno ,&nbsp;Akane Kanamori ,&nbsp;Yuji Miyatake ,&nbsp;Masahiro Oka ,&nbsp;Keisuke Ishii ,&nbsp;Tadashi Matsuura ,&nbsp;So Nakagawa ,&nbsp;Atsushi Hirao ,&nbsp;Makoto Onizuka ,&nbsp;Ai Kotani","doi":"10.1016/j.redox.2025.103727","DOIUrl":"10.1016/j.redox.2025.103727","url":null,"abstract":"<div><div>Iron is essential for neoplasms including natural killer (NK) cell lymphoma, and mainly supplemented by transferrin and stored by ferritin. Although accumulating studies had demonstrated that iron chelation arrests cell cycle progression at G1 phase, our previous studies showed the induction of DNA double strand break at S phase cell cycle without G1 arrest by selective inhibition of cellular transferrin uptake, indicating that the existence of some undiscovered differences in the roles of the two major iron sources for cell cycle regulation. In this study, we identified a novel cell cycle regulation of transferrin binding iron in NK cell lymphoma. Blocking transferrin uptake induced S phase arrest owing to the dysfunction of nascent DNA synthesis. Moreover, canonical G1 arrest was observed with mitochondrial dysfunction followed by downregulation of mTORC1 and dephosphorylation of Rb only when intracellular iron storage was deprived by iron chelation. These results suggested that iron is critically involved in at least two steps of the cell cycle: the S phase and G1/S transition. Especially, considering the toxicity of mitochondrial dysfunction to normal cells and cell cycle dependent manner of S phase-specific DNA damage due to selective inhibition of transferrin uptake, transferrin receptor blockers are thought to be more suitable than iron chelators as antineoplastic agents. Overall, the current canonical model of cell cycle regulation by iron requires revision.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"85 ","pages":"Article 103727"},"PeriodicalIF":10.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298729","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}