Redox Biology最新文献

{"title":"Gp93 safeguards tissue homeostasis by preventing ROS-JNK-mediated apoptosis","authors":"Meng Xu ,&nbsp;Wanzhen Li ,&nbsp;Ruihong Xu ,&nbsp;Lixia Liu ,&nbsp;Zhihan Wu ,&nbsp;Wenzhe Li ,&nbsp;Chao Ma ,&nbsp;Lei Xue","doi":"10.1016/j.redox.2025.103537","DOIUrl":"10.1016/j.redox.2025.103537","url":null,"abstract":"<div><div>Reactive oxygen species (ROS) play a pivotal role in maintaining tissue homeostasis, yet their overabundance can impair normal cellular functions, induce cell death, and potentially lead to neurodegenerative disorders. This study identifies <em>Drosophila</em> Glycoprotein 93 (Gp93) as a crucial factor that safeguards tissue homeostasis and preserves normal neuronal functions by preventing ROS-induced, JNK-dependent apoptotic cell death. Firstly, loss of <em>Gp93</em> induces JNK-dependent apoptosis primarily through the induction of ROS. Secondary, neuro-specific depletion of <em>Gp93</em> results in ROS-JNK-mediated neurodegeneration. Thirdly, overexpression of Gp93 effectively curtails oxidative stress and neurodegeneration caused by paraquat exposure or the aging process. Furthermore, these functions of Gp93 can be substituted by its human ortholog, HSP90B1. Lastly, depletion of <em>HSP90B1</em> in cultured human cells triggers ROS production, JNK activation, and apoptosis. Thus, this study not only unveils a novel physiological function of Gp93, but also provides valuable insights for understanding the physiological and pathological functions of human HSP90B1.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103537"},"PeriodicalIF":10.7,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143422671","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":"Oxidative stress-mediated abnormal polarization of decidual macrophages promotes the occurrence of atonic postpartum hemorrhage","authors":"Jiangxue Qu ,&nbsp;Hai Jiang ,&nbsp;Boyang Zhang ,&nbsp;Huifeng Shi ,&nbsp;Shuai Zeng ,&nbsp;Wei Wang ,&nbsp;Lian Chen ,&nbsp;Yangyu Zhao","doi":"10.1016/j.redox.2025.103530","DOIUrl":"10.1016/j.redox.2025.103530","url":null,"abstract":"<div><div>Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. However, the mechanism underlying atonic PPH remains partially elucidated. Multi-omics revealed that differentially expressed proteins and metabolites were enriched in the immune-inflammation pathway in the vaginal blood of patients with atonic PPH. There was a pro-inflammatory immune microenvironment primarily activated by M1 macrophages in the decidua of the patients with atonic PPH, which presented as increased tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 levels and affected the contraction of the uterine smooth muscle. Besides, the decidual macrophage of the atonic PPH group exhibited increased oxidative stress. The PPH decidual cell culture medium induced the polarization of peripheral blood monocytes towards M1 macrophages while markedly increasing the levels of reactive oxygen species and superoxide anion radical. Using hydrogen peroxide (H₂O₂) to stimulate decidual macrophages induced a similar polarization state to that in atonic PPH samples, and the secretion of pro-inflammatory cytokines, such as TNF-α and IL-8, was significantly upregulated, which markedly impacted the expression of contraction-associated proteins (CAPs) in the uterine smooth muscle cells (uSMCs). The animal model suggested that H₂O₂ promoted the polarization of placental macrophages towards M1, affecting the levels of placental oxidative stress and inflammatory infiltration, and the contractility of uterine smooth muscle tissues. In summary, abnormal oxidative stress at the maternal-fetal interface induced the M1 polarization of decidual macrophages, causing the secretion of pro-inflammatory cytokines. TNF-α and IL-8 acted on uSMCs to inhibit CAP expression, inducing atonic PPH.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103530"},"PeriodicalIF":10.7,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479181","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":"Complex I superoxide anion production is necessary and sufficient for complex I inhibitor-induced dopaminergic neurodegeneration in Caenorhabditis elegans","authors":"Katherine S. Morton,&nbsp;Alex J. George,&nbsp;Joel N. Meyer","doi":"10.1016/j.redox.2025.103538","DOIUrl":"10.1016/j.redox.2025.103538","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is the 2^nd most prevalent neurodegenerative disease, but there is currently no cure and limited understanding of the pathogenesis resulting in dopaminergic neurodegeneration. Inhibitors of electron transport chain Complex I (CI) have long been associated with and are now used to model PD, but CI inhibition results in multiple effects including ATP depletion and reactive oxygen species (ROS) generation. The lack of tools to isolate effects of CI inhibition have rendered it difficult to determine which mechanistic step is critical for CI inhibitor-induced dopaminergic neurodegeneration. Here we report that CI-derived superoxide anion, not ATP depletion, is the critical driver of CI inhibitor-induced dopaminergic neurodegeneration in the model organism <em>Caenorhabditis elegans</em>. We first use SuperNova, a light-activated ROS-generating protein, fused to CI to demonstrate that in absence of enzymatic inhibition CI-localized ROS production is sufficient to drive morphological damage and loss of function of the dopaminergic neurons. Second, we prevented superoxide anion production during exposure to the CI inhibitors rotenone and pyridaben and report a full rescue of CI inhibitor-induced degeneration and functional loss, without rescue of inhibitor-induced ATP depletion. We highlight the importance of mitochondrial superoxide anion generation in the pathogenesis of PD and build a foundation for further definition of the pathways activated by mitochondrial ROS that led to neuronal dysfunction and death. Identification of these underlying mechanisms allows for future prevention of toxicant exposure-induced PD based on mechanistic knowledge.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103538"},"PeriodicalIF":10.7,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403297","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":"Swimming exercise induces redox-lipid crosstalk to ameliorate osteoarthritis progression","authors":"Yubin Wu ,&nbsp;Mingzhuang Hou ,&nbsp;Yaoge Deng ,&nbsp;Xiaowei Xia ,&nbsp;Yang Liu ,&nbsp;Jianfeng Yu ,&nbsp;Chenqi Yu ,&nbsp;Huilin Yang ,&nbsp;Yijian Zhang ,&nbsp;Xuesong Zhu","doi":"10.1016/j.redox.2025.103535","DOIUrl":"10.1016/j.redox.2025.103535","url":null,"abstract":"<div><div>Conventional pharmacotherapy exhibits limited efficacy in halting cartilage degeneration, whereas exercise interventions have demonstrated promising protective effects against osteoarthritis (OA), albeit with unclear underlying mechanisms. This study investigated the beneficial effects of swimming in mitigating local joint damage through the enhancement of systemic antioxidant capacity. We found that overexpression of superoxide dismutase 3 (SOD3) could promote the elimination of extracellular reactive oxygen species (ROS) and preserve the cartilage extracellular matrix (C-ECM). Conversely, genetic deletion of SOD3 accelerated the loss of C-ECM and contributed to OA due to an imbalance in extracellular oxidative stress. Further investigation revealed that SOD3 could interact with CCAAT/enhancer binding protein β (C/EBPβ), leading to the inhibition of apolipoprotein E (APOE) transcription and subsequent APOE-induced cholesterol transport. Ultimately, we developed targeted extracellular vesicles (EVs) with high cartilage affinity for efficient and precise delivery of SOD3. Overall, this study elucidated the potential of exercise for degenerative joint disorders through SOD3-mediated extracellular antioxidation and cholesterol redistribution.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103535"},"PeriodicalIF":10.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403295","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":"Quantitative analysis of the proteome and protein oxidative modifications in primary human coronary artery endothelial cells and associated extracellular matrix","authors":"Shuqi Xu ,&nbsp;Christine Y. Chuang ,&nbsp;Clare L. Hawkins ,&nbsp;Per Hägglund ,&nbsp;Michael J. Davies","doi":"10.1016/j.redox.2025.103524","DOIUrl":"10.1016/j.redox.2025.103524","url":null,"abstract":"<div><div>Vascular endothelial cells (ECs) play a key role in physiology by controlling arterial contraction and relaxation, and molecular transport. EC dysfunction is associated with multiple pathologies. Here, we characterize the cellular and extracellular matrix (ECM) proteomes of primary human coronary artery ECs, from multiple donors, and oxidation/nitration products formed on these during cell culture, using liquid chromatography-mass spectrometry. In total ∼9900 proteins were identified in cells from 3 donors, with ∼7000 proteins per donor. Of these ∼5300 were consistently identified, indicating some heterogeneity across the donors, with age a possible cause. Multiple endogenous oxidation products were detected on both ECM and cellular proteins (and particularly endoplasmic reticulum species). In contrast, nitration was mostly detected on cell proteins and particularly cytoskeletal proteins, consistent with intracellular generation of nitrating agents, possibly from endothelial nitric oxide synthase (eNOS) or peroxidase enzymes. The modifications are ascribed to both physiological enzymatic activity (hydroxylation at proline/lysine; predominantly on ECM proteins and especially collagens) and the formation of reactive species (oxidation at tryptophan/tyrosine/histidine; nitration at tryptophan/tyrosine). The identified sites are present on a limited number of peptides (104 oxidized; 23 nitrated) from a modest number of proteins. A small number of proteins were detected with multiple modifications, consistent with these being selective and specific targets. Several nitrated peptides were consistently detected across all donors, and also in human smooth muscle cells suggesting that these are major targets in the vascular proteome. These data provide a ‘background’ proteome dataset for studies of endothelial dysfunction in disease.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103524"},"PeriodicalIF":10.7,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403308","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":"The structural integrity of human TFF1 under reducing conditions","authors":"Dilsah Nur Elmaci ,&nbsp;Gene Hopping ,&nbsp;Werner Hoffmann ,&nbsp;Markus Muttenthaler ,&nbsp;Matthias Stein","doi":"10.1016/j.redox.2025.103534","DOIUrl":"10.1016/j.redox.2025.103534","url":null,"abstract":"<div><div>The trefoil factor family (TFF) comprises three secretory peptides (TFF1, TFF2, TFF3) that regulate diverse physiological processes to maintain gastrointestinal mucosal integrity and homeostasis. The TFF domain is stabilized by six conserved cysteine residues forming three intramolecular disulfide bonds. In this work, we investigated human TFF1 domain stability against increasing concentrations of the reducing agent tris(2-carboxyethyl)phosphine (TCEP). Experiments revealed high resistance of the disulfide bonds within the TFF1 domain to reduction compared to two reference peptides with similar three-disulfide frameworks, namely the bovine pancreatic trypsin inhibitor (BPTI) and the peptide drug linaclotide. Full reduction of TFF1 was only achieved with a large excess of TCEP (150-fold), and no partially reduced intermediates were observed, supporting a compact TFF1 domain. This TFF1 domain stability was supported by extensive all-atom molecular dynamics simulations for a total of 24 μs of all possible combinatorial states of disulfide bond reduction. Despite minor structural and conformational changes observed upon reduction, the domain substantially retained its overall compactness and solvent exposure when only one or two disulfide bonds were removed. The reduced cysteine residues did not undergo large structural rearrangements and remained buried. The loss of covalent disulfide bonds upon reduction was counterbalanced through persistent non-covalent interactions. These molecular simulations explained why TFF1 could not be partially reduced and alkylated during the experiments despite titrating different TCEP concentrations in the presence of alkylating agents. Our findings provide the first insights into the remarkable stability of the human TFF domain under reducing conditions, supporting its functional resilience upon expression and secretion throughout the human body.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103534"},"PeriodicalIF":10.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438243","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":"Inhibition of S100A8/A9 ameliorates neuroinflammation by blocking NET formation following traumatic brain injury","authors":"Guihong Shi ,&nbsp;Yiyao Cao ,&nbsp;Jianye Xu ,&nbsp;Bo Chen ,&nbsp;Xu Zhang ,&nbsp;Yanlin Zhu ,&nbsp;Liang Liu ,&nbsp;Xilei Liu ,&nbsp;Luyuan Zhang ,&nbsp;Yuan Zhou ,&nbsp;Shenghui Li ,&nbsp;Guili Yang ,&nbsp;Xiao Liu ,&nbsp;Fanglian Chen ,&nbsp;Xin Chen ,&nbsp;Jianning Zhang ,&nbsp;Shu Zhang","doi":"10.1016/j.redox.2025.103532","DOIUrl":"10.1016/j.redox.2025.103532","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) triggers a robust inflammatory response that is closely linked to worsened clinical outcomes. S100A8/A9, also known as calprotectin or myeloid-related protein-8/14 (MRP8/14), is an alarmin primarily secreted by activated neutrophils with potent pro-inflammatory property. In this study, we explored the roles of S100A8/A9 in modulating neuroinflammation and influencing TBI outcomes, delving into the underlying mechanisms. S100A8/A9-enriched neutrophils were present in the injured brain tissue of TBI patients, and elevated plasma levels of S100A8/A9 were correlated with poorer neurological function. Furthermore, using a TBI mouse model, we demonstrated that treatment with the selective S100A8/A9 inhibitor Paquinimod significantly mitigated neuroinflammation and neuronal death, thereby improving the prognosis of TBI mice. Mechanistically, we found that S100A8/A9, in conjunction with neutrophil activation and infiltration into the brain, enhances reactive oxygen species (ROS) production within neutrophils, accelerating PAD4-mediated neutrophil extracellular trap (NET) formation, which in turn exacerbates neuroinflammation. These findings suggest that S100A8/A9 amplifies neuroinflammatory responses by promoting NET formation in neutrophils. Inhibition of S100A8/A9 effectively attenuated NET-mediated neuroinflammation; however, when PAD4 was overexpressed in the brain using adenovirus, leading to an increased formation of NET in the brain, the anti-inflammatory effects of S100A8/A9 inhibition were markedly diminished. Further experiments with PAD4 knockout mice confirmed that the reduction of NETs could substantially alleviate S100A8/A9-driven neuroinflammation. Finally, we established that the suppression of NET formation by S100A8/A9 inhibition is primarily mediated through the AMPK/Nrf2/HO-1 signaling pathway. These findings underscore the critical pathological role of S100A8/A9 in TBI and emphasize the need for further exploration of S100A8/A9 inhibitor Paquinimod as a potential therapeutic strategy for TBI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103532"},"PeriodicalIF":10.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373070","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":"The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation","authors":"James N. Cobley ,&nbsp;Panagiotis N. Chatzinikolaou ,&nbsp;Cameron A. Schmidt","doi":"10.1016/j.redox.2025.103523","DOIUrl":"10.1016/j.redox.2025.103523","url":null,"abstract":"<div><div>The post-translational redox regulation of protein function by cysteine oxidation controls diverse biological processes, from cell division to death. However, most current site-centric paradigms fail to capture the nonlinear and emergent nature of redox regulation in proteins with multiple cysteines. Here, we present a proteoform-centric theory of redox regulation grounded in the <em>i</em>-space. The <em>i</em>-space encapsulates the theoretical landscape of all possible cysteine proteoforms. Using computational approaches, we quantify the vast size of the abstract <em>i</em>-space, revealing its scale-free architecture—elucidating the disproportionate influence of cysteine-rich proteins. We define mathematical rules governing cysteine proteoform dynamics. Their dynamics are inherently nonlinear, context-dependent, and fundamentally constrained by protein copy numbers. Monte Carlo simulations of the human protein PTP1B reveal extensive <em>i</em>-space sampling beyond site-centric models, supporting the “oxiform conjecture”. This conjecture posits that highly oxidised proteoforms, molecules bearing multiple oxidised cysteines, are central to redox regulation. In support, even 90%-reduced proteomes can house vast numbers of unique, potentially functioanlly diverse, oxiforms. This framework offers a transformative lens for understanding the redox biology of proteoforms.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103523"},"PeriodicalIF":10.7,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373071","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":"ProteotoxomiRs: Diagnostic and pathologic miRNA signatures for reductive stress induced proteotoxic heart disease","authors":"Santhosh Kumar Karthikeyan ,&nbsp;Palanisamy Nallasamy ,&nbsp;Jarrell Matthew Cleveland ,&nbsp;Ahila Arulmani ,&nbsp;Ashvanthi Raveendran ,&nbsp;Mariam Karimi ,&nbsp;Mohammad Owais Ansari ,&nbsp;Anil Kumar Challa ,&nbsp;Moorthy P. Ponnusamy ,&nbsp;Ivor J. Benjamin ,&nbsp;Sooryanarayana Varambally ,&nbsp;Namakkal S. Rajasekaran","doi":"10.1016/j.redox.2025.103525","DOIUrl":"10.1016/j.redox.2025.103525","url":null,"abstract":"<div><div>Proteotoxic stress progressively leads to irreversible cardiac abnormalities. Using a mouse model of reductive stress-induced proteotoxic cardiomyopathy, we identified novel microRNA signatures, termed “ProteotoxomiRs,” which reflect stage-specific and transgene-specific responses to proteotoxic stress. Seven microRNAs were uniquely linked to the human mutant R120G-αB-Crystallin transgene, indicating their direct association with the pathogenic protein. Additionally, we uncovered two distinct microRNA profiles associated with the early (pre-onset) and late (cardiomyopathy/heart failure) stages of disease progression. Early-stage signatures primarily modulate signaling pathways essential for cardiac health, including mTOR and MAPK, while late-stage signatures reveal regulatory disruptions in calcium signaling and autophagy insufficiency, driving irreversible cardiac damage caused by reductive stress (RS) and proteotoxicity in transgenic mice. These findings reveal stage-specific miRNA biomarkers with potential diagnostic and prognostic value, offering new insights into the molecular underpinnings of proteotoxic cardiac disease. Moreover, our miRNA-mRNA interaction analysis uncovered potential targets unique to the transgene-specific, early, and late stages of the disease, including several promising druggable candidates, warranting further validation for translational applications.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"81 ","pages":"Article 103525"},"PeriodicalIF":10.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452945","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":"Genetic interaction between oxidative stress and body mass index in a Spanish population","authors":"Francisco Lara-Hernández ,&nbsp;Rebeca Melero ,&nbsp;María Elena Quiroz-Rodríguez ,&nbsp;Celeste Moya-Valera ,&nbsp;Mariana de Jesús Gallardo-Espinoza ,&nbsp;Luis Álvarez ,&nbsp;Ingrid Lizeth Valarezo-Torres ,&nbsp;Laisa Briongos-Figuero ,&nbsp;Jessica Abadía-Otero ,&nbsp;Francisco Javier Mena-Martin ,&nbsp;Guillermo Saez ,&nbsp;Josep Redon ,&nbsp;Juan-Carlos Martín-Escudero ,&nbsp;Ana-Bárbara García-García ,&nbsp;Guillermo Ayala ,&nbsp;Felipe Javier Chaves","doi":"10.1016/j.redox.2025.103531","DOIUrl":"10.1016/j.redox.2025.103531","url":null,"abstract":"<div><div>Oxidative stress may act as a contributing factor in the development of an elevated body mass index (BMI). Oxidative stress has the potential to modulate genetic activity at various levels, including gene transcription and protein function regulation. Nevertheless, the interplay between genetic variants and oxidative stress in relation to BMI remains to be elucidated. Based on this premise, we studied the potential association between 723 single-nucleotide polymorphisms (SNPs) located within a set of 212 genes and both BMI and oxidative stress parameters in 1502 adults from the general Spanish population (Hortega Study). Oxidative stress parameters measured included malondialdehyde (MDA) levels, 8-oxo-2′-deoxyguanosine (8-oxo-dG) levels and oxidised/reduced glutathione ratio (GSSG/GSH). We also examined the potential impact of the interaction between these SNPs and oxidative stress levels on BMI. The genes selected regulate several key biological processes, including obesity, blood pressure, inflammation, lipid metabolism and redox homeostasis. Our findings indicate a robust association between specific genes and both BMI and oxidative stress parameters. Significant BMI-related interactions between genes and oxidative stress parameters were identified, which have a multifactorial impact on oxidative stress modulation and on BMI. SNPs identified in genes such as <em>NPPA</em>, <em>CPT1A</em>, <em>DDIT3</em>, <em>NOX</em> and <em>IL6ST</em> were significantly associated with all oxidative stress parameters analysed, indicating a substantial influence on BMI modulation. The results provide compelling evidence of a significant relationship between oxidative stress levels and genetic background. Our data provide new insights into BMI modulation by oxidative stress levels, highlighting a role for <em>TNF</em> as a key player in the interrelation of oxidative stress and BMI.</div></div>","PeriodicalId":20998,"journal":{"name":"Redox Biology","volume":"80 ","pages":"Article 103531"},"PeriodicalIF":10.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372982","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}