Gene最新文献

{"title":"Cloning, biochemical identification and characterization of purine nucleoside N-ribohydrolase in Levilactobacillus brevis","authors":"Mokhammad Khoiron Ferdiansyah ,&nbsp;Seung Hyeon Ji ,&nbsp;Beomseok Park ,&nbsp;Yong Hwi Kwon ,&nbsp;Myeong Seong Cha ,&nbsp;Gaddapara Manasa ,&nbsp;Kwang-Pyo Kim","doi":"10.1016/j.gene.2025.149804","DOIUrl":"10.1016/j.gene.2025.149804","url":null,"abstract":"<div><div>Purine nucleoside N-ribohydrolase (PNase) plays a crucial role in purine metabolism and possibly in hyperuricemia management by degrading purine nucleosides. However, the genetic basis of the enzyme activity in lactic acid bacteria (LAB) remains largely unexplored. This study aimed to clone and express four putative PNase genes from<!--> <em>Levilactobacillus brevis</em> <!-->LABC170, and to identify the gene(s) responsible for degrading adenosine, guanosine, and inosine. Furthermore, we studied optimal reaction conditions and enzyme kinetics. The four putative PNase genes were cloned, and enzymatic activity was evaluated by high-performance liquid chromatography (HPLC). The optimal pH and temperature were determined, and kinetic parameters were analyzed. Among the candidates, the recombinant PNase 3 gene product exhibited purine nucleosidase activity with optimal activity at pH 7 and temperatures between 35 and 40 °C, while it failed to degrade pyrimidine nucleosides. Kinetic analysis showed the turnover number for adenosine, with a Kcat of 2.18 × 10³ ± 2.29 × 10² min⁻¹ and a catalytic efficiency of 2.79 × 10⁴ ± 2.94 × 10³ mM⁻¹·min⁻¹, followed by guanosine and inosine. PNase 3 from<!--> <em>L. brevis</em> <!-->LABC170 demonstrates promising potential for hyperuricemia management and application in functional foods aimed at modulating purine metabolism.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"970 ","pages":"Article 149804"},"PeriodicalIF":2.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SlIAA9 negatively regulates tomato (Solanum lycopersicum) tolerance to drought stress","authors":"Xiaoyu Cao ,&nbsp;Wenqi Li ,&nbsp;Aiqi Ren ,&nbsp;Chuyan Ji ,&nbsp;Xiangqiang Zhan ,&nbsp;Tixu Hu","doi":"10.1016/j.gene.2025.149788","DOIUrl":"10.1016/j.gene.2025.149788","url":null,"abstract":"<div><div>The Aux/IAA (auxin/indole-3-acetic acid) gene family coordinates many key processes in the adaptive growth of plants. However, limited information is available about the regulatory mechanism of <em>SlIAA9</em> (<em>Solyc04g076850</em>), which is a member of the Aux/IAAs. The goal of this study was to analyze the pattern of expression and regulatory mechanism of <em>SlIAA9</em> in detail. The promoter of <em>SlIAA9</em> gene with 1600 bp upstream of ATG was cloned from tomato (<em>Solanum lycopersicum</em> cv. Ailsa Craig). The promoter analysis suggests that abiotic stressors and phytohormones may stimulate the expression of <em>SlIAA9</em>. Furthermore, we confirmed that the <em>SlIAA9</em> transcript was induced by auxin, gibberellin, salicylic acid, abscisic acid, methyl jasmonate, heat, cold, drought, and salt stress. We preliminarily found that <em>SlIAA9</em> plays a negative role in the drought signaling response by affecting the ability to scavenge reactive oxygen species. To analyze the function of the <em>SlIAA9</em> promoter in more detail, we created the <em>proSlIAA9</em>:<em>GUS</em> transgenic tomato line. GUS staining showed that the <em>SlIAA9</em> promoter was highly active in the roots, leaves, sepals, petals and anthers of tomato seedlings. The promoter was expressed the most highly in the flowers. To further verify the activity of the <em>SlIAA9</em> promoter, we found that different segments of the <em>SlIAA9</em> promoter had different regulatory effects on the expression of downstream genes in response to IAA. A 400 bp fragment was identified as the key functional region for IAA response.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"970 ","pages":"Article 149788"},"PeriodicalIF":2.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic analysis of a family with skeletal muscle ion channelopathy and hereditary spastic paraplegia type 7 caused by SCN4A and SPG7 double mutations","authors":"Hong-ping Yu ,&nbsp;Zi-yan Xu ,&nbsp;Meng-qian Wu ,&nbsp;Qian Chen ,&nbsp;Zhi-hai Zheng ,&nbsp;Wen Wei ,&nbsp;Pan Lin ,&nbsp;Jing Zou ,&nbsp;Jian-hui Zhang ,&nbsp;Dan-dan Ruan ,&nbsp;Ruo-li Wang ,&nbsp;Li Chen ,&nbsp;Mei-zhu Gao ,&nbsp;Li Zhang ,&nbsp;Li-sheng Liao ,&nbsp;Fan Lin ,&nbsp;Hong Li ,&nbsp;Zhu-ting Fang ,&nbsp;Wei Wang ,&nbsp;Xing-lin Ruan ,&nbsp;Yun-fei Li","doi":"10.1016/j.gene.2025.149782","DOIUrl":"10.1016/j.gene.2025.149782","url":null,"abstract":"<div><div>Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous neurodegenerative disorder, primarily defined by progressive lower-limb spasticity and weakness. Among the numerous genes implicated, pathogenic variants in the <em>spastic paraplegia 7</em> (<em>SPG7</em>) gene represent one of the most common causes of HSP, whereas mutations in <em>SCN4A</em>, a skeletal muscle ion channel gene, are typically associated with a diverse spectrum of phenotypes, including hyperkalemic and hypokalemic periodic paralysis, potassium-aggravated myotonia, and congenital paramyotonia. To date, however, the coexistence of pathogenic variants in <em>SPG7</em> and <em>SCN4A</em> within the same pedigree, and their potential pathogenic interplay, has not been documented.</div><div>In this study, we performed comprehensive genetic profiling, including whole-exome sequencing, mitochondrial genome analysis, dynamic mutation screening, copy number variation assessment, and Sanger sequencing. We identified a novel heterozygous <em>SPG7</em> variant (c.578A&gt;G; p.E193G) alongside a known pathogenic <em>SCN4A</em> missense mutation (c.2111C&gt;T; p.T704M). Remarkably, individuals harboring both variants presented with highly complex phenotypes that combined classical HSP manifestations with ion channel dysfunctions, such as congenital paramyotonia and hypokalemic periodic paralysis.</div><div>These findings provide the first evidence of a possible genetic interaction between <em>SPG7</em> and <em>SCN4A</em>, expanding the recognized clinical and molecular spectrum of HSP. Our results underscore the diagnostic value of multi-gene testing in patients with atypical or overlapping neuromuscular symptoms and highlight the importance of considering potential polygenic contributions when interpreting the clinical heterogeneity of HSP.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"971 ","pages":"Article 149782"},"PeriodicalIF":2.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective role of Lactobacillus plantarum in Eimeria tenella infection: Impact on hematological, inflammatory, and apoptotic gene responses","authors":"Muhammad Mohsin ,&nbsp;Yusra Afzal ,&nbsp;Muhammad Tahir Aleem ,&nbsp;Mubashar Hassan ,&nbsp;Aftab Shaukat ,&nbsp;Farman Ali ,&nbsp;Asghar Abbas ,&nbsp;Rao Zahid Abbas ,&nbsp;Majid Khan ,&nbsp;Muhammad Asmat Ullah Saleem ,&nbsp;Assar Ali Shah ,&nbsp;Khawar Hayat ,&nbsp;Guangwen Yin","doi":"10.1016/j.gene.2025.149783","DOIUrl":"10.1016/j.gene.2025.149783","url":null,"abstract":"<div><div>Coccidiosis, a major parasitic disease in poultry, causes substantial economic losses worldwide. The rise of drug-resistant <em>Eimeria</em> strains has intensified the need for alternative control measures. This study evaluated the probiotic <em>Lactobacillus plantarum</em> (<em>L. plantarum</em>) as a dietary supplement to protect chickens from <em>Eimeria tenella</em> (<em>E. tenella</em>) infection. We examined its effects on growth performance, disease severity, cecal lesions, oocyst scores, immune response, haematological parameters, and the expression of genes related to inflammation and apoptosis. The levels of pro-inflammatory cytokines (IL-6 and IL-8) and apoptosis-related proteins (Bax, Bcl-2, and caspase-3) were measured by mRNA expression. Probiotic-supplemented groups downregulated the mRNA expression levels of the pro-apoptosis protein Bax. They up-regulated the mRNA expression levels of the anti-apoptosis protein Bcl-2 more than those of the control groups. The findings also showed a statistically higher lymphoproliferative (P &lt; 0.05) response in the probiotics @1.5 × 10⁸ CFU)-supplemented group in feed compared to the control group. The probiotics administered in the feed groups showed reduced oocysts shedding, fewer intestinal lesions, and improved hematological parameters than the control (<em>E. tenella</em> infected, non-treated) group. The research showed that probiotic supplementation without anticoccidial drugs could protect chickens against the adverse effects of <em>E. tenella.</em></div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"970 ","pages":"Article 149783"},"PeriodicalIF":2.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole exome sequencing study of families with single atrium and/or single ventricle identifies de novo mutations in CORIN and TTLL10 as potential pathogenic genes","authors":"Yi Wu ,&nbsp;Wuqian Wang ,&nbsp;Wei Zhou ,&nbsp;Baoying Ye ,&nbsp;Luan Chen ,&nbsp;Ping Tang ,&nbsp;Jiamin Niu ,&nbsp;Xia Han ,&nbsp;Xiaofang Sun ,&nbsp;Shengying Qin ,&nbsp;Yanlin Wang","doi":"10.1016/j.gene.2025.149786","DOIUrl":"10.1016/j.gene.2025.149786","url":null,"abstract":"<div><h3>Background</h3><div>Single atrium and/or single ventricle (SA and/or SV) are severe congenital heart malformations linked to gene mutations, though the underlying genetic mechanisms remain unclear. This study seeks to elucidate these mechanisms. <em>Methods:</em> Trio-whole exome sequencing (trio-WES) was performed to identify <em>de novo</em> mutations in 36 familial SA/SV cases. Identified genes were analyzed using Gene Ontology (GO), KEGG pathways, and protein–protein interaction (PPI) analyses. Pathogenicity predictions were performed using established databases, and key <em>de novo</em> mutations were validated via Sanger sequencing. Zebrafish morpholino (MO) knockdown experiments were utilized to assess the functional impact of candidate genes.</div></div><div><h3>Results</h3><div>Trio-WES analysis identified 183 candidate genes harboring <em>de novo</em> single nucleotide variants (SNVs), with 24 genes linked to congenital heart disease (CHD) and enriched in the heart morphogenesis signaling pathway. Screening through a deleterious variants database revealed ten <em>de novo</em> SNVs, eight of which were confirmed by Sanger sequencing. Subsequent screening using mouse, zebrafish, and cardiac single-cell databases highlighted two genes: <em>CORIN</em> and <em>TTLL10</em>. Zebrafish knockdown experiments showed cardiac defects and altered heart rate, supporting their involvement in SA/SV development.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that mutations in <em>de novo</em> genes play a critical role in cardiac development, offering insights into SA/SV mechanisms and potential diagnostic targets.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"970 ","pages":"Article 149786"},"PeriodicalIF":2.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual role and ceRNA networks of miR-146a in lung cancer: regulating proliferation, metastasis, and chemoresistance","authors":"Jingyuan Wang ,&nbsp;Yueyou Wang ,&nbsp;Langping Li ,&nbsp;Zhijun Lu ,&nbsp;Zhongliang Ma","doi":"10.1016/j.gene.2025.149773","DOIUrl":"10.1016/j.gene.2025.149773","url":null,"abstract":"<div><div>Lung cancer persists as the predominant cause of cancer-related mortality globally. MicroRNAs, a class of short non-coding RNAs, are recognized as critical regulators in the pathogenesis of lung cancer, functioning either as oncogenes or tumor suppressors. Among these, miR-146a has been identified as a significant modulator in non-small-cell lung cancer, exerting influence over cellular proliferation, resistance to chemotherapy, apoptosis, and metastatic potential. Notably, miR-146a displays a dualistic role, acting as either a tumor suppressor or an oncogene depending on the molecular mechanisms. Furthermore, its interaction with non-coding RNAs—including circular and long non-coding RNAs—through a competing endogenous RNA network contributes additional regulatory complexity. Dysregulation of miR-146a–associated ceRNA networks influences tumor proliferation, invasion, immune evasion, and therapy resistance. Despite the breadth of existing research, the mechanisms underlying this dual behavior remain insufficiently clarified. This review synthesizes current findings regarding miR-146a’s bidirectional functions and explores its potential clinical applications as both a diagnostic marker and a therapeutic target in lung cancer.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"970 ","pages":"Article 149773"},"PeriodicalIF":2.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editor's corner: Unmasking deep intronic variants.","authors":"Matija Rijavec","doi":"10.1016/j.gene.2025.149781","DOIUrl":"https://doi.org/10.1016/j.gene.2025.149781","url":null,"abstract":"","PeriodicalId":12499,"journal":{"name":"Gene","volume":" ","pages":"149781"},"PeriodicalIF":2.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapy-induced senescence in prostate cancer: Mechanisms, therapeutic strategies, and clinical implications.","authors":"Luisa Bacca, Julian Brandariz, Francesca Zacchi, Andrea Zivi, Joaquin Mateo, David P Labbé","doi":"10.1016/j.gene.2025.149774","DOIUrl":"https://doi.org/10.1016/j.gene.2025.149774","url":null,"abstract":"<p><p>Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, particularly in its advanced and metastatic stages. While various systemic therapies have improved clinical outcomes, therapy resistance and disease progression remain significant challenges. One critical, yet underappreciated, mechanism influencing treatment response is therapy-induced senescence (TIS), a stable form of cell cycle arrest triggered by anticancer treatments. In PCa, TIS can be elicited by chemotherapy, radiotherapy, hormonal therapies, and targeted agents, and is characterized by a complex interplay of tumor-suppressive and tumor-promoting effects, largely mediated through the senescence-associated secretory phenotype (SASP). This review explores the molecular mechanisms of senescence, the diverse therapeutic strategies that induce it, and the dual roles it plays in PCa progression and treatment resistance. We further discuss emerging approaches that combine senescence-inducing therapies with senescence-targeting strategies, such as senolytics and senomorphics, to mitigate the adverse consequences of persistent senescent PCa cells. Finally, we highlight ongoing clinical trials, translational barriers, and future directions in integrating senotherapy into the clinical management of PCa.</p>","PeriodicalId":12499,"journal":{"name":"Gene","volume":" ","pages":"149774"},"PeriodicalIF":2.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of OsTTG1 influences seed size and silique length in Arabidopsis thaliana","authors":"Shuangshuang Luo ,&nbsp;Yanyan Wu ,&nbsp;Ju Gao ,&nbsp;Yongcheng Li ,&nbsp;Jianhui Liu ,&nbsp;Xiuzhong Xia ,&nbsp;Zongqiong Zhang ,&nbsp;Baoxuan Nong ,&nbsp;Rui Feng ,&nbsp;Can Chen ,&nbsp;Hui Guo ,&nbsp;Dekun Lei ,&nbsp;Weihao Wang ,&nbsp;Zhigan Xie ,&nbsp;Wenhui Jiang ,&nbsp;Danting Li ,&nbsp;Xinghai Yang","doi":"10.1016/j.gene.2025.149784","DOIUrl":"10.1016/j.gene.2025.149784","url":null,"abstract":"<div><div>Seed size is a critical factor affecting seed yield and has been one of the primary objectives of plant breeders since the domestication of crop plants. In <em>Arabidopsis</em> (<em>Arabidopsis thaliana</em> (L.) Heynh.), <em>TRANSPARENT TESTA GLABRA1</em> (<em>AtTTG1</em>, <em>At5G24520</em>) has been confirmed to be associated with seed size. However, whether <em>Oryza sativa TRANSPARENT TESTA GLABRA 1</em> (<em>OsTTG1</em>, <em>LOC_Os02g45810</em>) affects seed size has not been reported. In this study, we obtained <em>A. thaliana</em> transgenic lines expressing <em>OsTTG1</em> via the floral dip method. We found that <em>OsTTG1</em> effectively restored the defective phenotypes of small seeds and short siliques exhibited by this mutant. Compared with the ttg1 mutant, <em>A. thaliana</em> seeds from the <em>OsTTG1</em>-OE lines showed significantly increased grain length (2–56 %), grain width (3–55 %), 100-grain weight (19–58 %), silique length (15–33 %), and the number of seeds per silique (11–73 %) compared with the <em>ttg1</em> mutant. In contrast, there were no significant differences between the <em>OsTTG1</em>-OE strain and the wild type for any of the traits, except for slightly smaller grain length and width. These results suggest that <em>OsTTG1</em> plays an important role in the regulation of seed and silique development. To further investigate the mechanism by which <em>OsTTG1</em> influences seed size and silique length, we performed RNA-seq analysis on samples from the early, middle, and late pod-setting stages of the three genotypes. In |log₂ (Fold Change) | ≥ 1 and the adjusted <em>P</em>-value &lt; 0.05, we identified multiple DEGs (<em>CYP72C1</em>, <em>CYP78A5</em>, <em>CYP78A9</em>, <em>ABI5</em>, <em>STK</em>, <em>TTG2</em>, <em>MEA</em>, <em>MET1</em>, <em>RR21</em>, <em>AP2</em>) that may be related to seed size and silique length. <em>OsTTG1</em> may directly or indirectly affect the expression of the above genes, which in turn affects seed size. Altogether, our results demonstrate that <em>OsTTG1</em> can positively regulate seed size and silique length.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"970 ","pages":"Article 149784"},"PeriodicalIF":2.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menaquinone-4 ameliorates abdominal aortic aneurysm by suppressing ferroptosis through NRF2/GCLM axis","authors":"Zhihao Zhou ,&nbsp;Lin Huang ,&nbsp;Dan Wu ,&nbsp;Rongzhou He ,&nbsp;Yu Zhou ,&nbsp;Kangjie Wang ,&nbsp;Rui Wang ,&nbsp;Chen Yao","doi":"10.1016/j.gene.2025.149785","DOIUrl":"10.1016/j.gene.2025.149785","url":null,"abstract":"<div><div>Abdominal aortic aneurysm (AAA) remains a lethal vascular disease lacking effective pharmacotherapies, with ferroptosis emerging as a critical pathological mechanism. This study explored the therapeutic potential of menaquinone-4 (MK4), a vitamin K2 isoform, in both porcine pancreatic elastase-induced AAA mice and Erastin-treated vascular smooth muscle cells (VSMCs). Our investigations revealed that MK4 treatment significantly attenuated AAA progression, reducing aortic dilation while maintaining vascular structural integrity. Importantly, MK4 demonstrated an excellent safety profile in all experimental models, including serum biomarker analysis. Mechanistically, MK4 exerted potent anti-ferroptotic effects in VSMCs by alleviating iron overload and reactive oxygen species (ROS) level, suppressing lipid peroxidation, and restoring glutathione homeostasis. Through RNA sequencing and chromatin immunoprecipitation assays, we identified that MK4 activates the nuclear factor erythroid-2 like 2 (NRF2)/glutamate-cysteine ligase modifier subunit (GCLM) pathway, with molecular docking confirming strong binding between MK4 and NRF2. The essential role of GCLM was validated using pharmacological inhibition, which completely abolished MK4’s protective effects. Clinical relevance was further supported by pathological iron accumulation and decreased GCLM expression in human AAA specimens compared to controls. These findings establish that MK4 inhibits AAA progression through NRF2-mediated transcriptional activation of GCLM to suppress ferroptosis, positioning it as a promising and clinically translatable therapeutic candidate for this devastating vascular disease.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"970 ","pages":"Article 149785"},"PeriodicalIF":2.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}