Journal of Advanced Research最新文献

{"title":"Integrated multi-omics analysis to elucidate the genetic basis of seed traits in cotton","authors":"Rumeng Zhao, Le Liu, Yuling Guo, Mengli Yu, Lili Lu, Jiajie Yang, Bowei Xu, Liqiang Fan, Zuoren Yang","doi":"10.1016/j.jare.2026.04.046","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.046","url":null,"abstract":"<h3>Introduction</h3>Seed size is a complex agronomic trait influencing seed germination, seedling vitality, and yield. The traditional single-omics strategy for identifying seed size-related genes has the disadvantage of low accuracy, limiting its potential application in molecular breeding.<h3>Objectives</h3>This study aimed to integrate multi-omics approaches to identify key genes and pathways regulating cotton seed size.<h3>Methods</h3>We employed 413 accessions of seeds from natural cotton populations to quantitatively obtain seed size-related phenotypes (length, width, area, roundness, perimeter, length-to-width ratio, and seed index) using phenomics technology. Dimensionality reduction was applied to seven phenotypic datasets to identify elements that can simultaneously map phenotypic traits. These were then combined with genomic data for genome-wide association studies (GWAS) to identify candidate genes. Representative accessions were screened by k-means clustering to construct differential gene expression profiles at different developmental stages, and a hub gene set was determined by WGCNA. Genes in QTL from GWAS and hub genes from WGCNA are co-localized to identify key genes, and gene functions are verified through genetic material construction and metabolomics analysis.<h3>Results</h3>The co-localization results from GWAS and transcriptomics efficiently and precisely identified a novel gene, <em>GhCSS10</em>. Constructed RNAi and overexpression transgenic lines confirmed their positive regulation of seed size. Metabolomics further demonstrated that variations in seed size are closely associated with metabolic processes, including cell energy activation, cell expansion, carbohydrate deposition, and seed filling.<h3>Conclusion</h3>The multi-omics integration strategy developed in this study effectively identifies key genes and metabolic pathways regulating cotton seed size. It provides a novel perspective for elucidating the molecular basis of cotton seed development and offers highly valuable targets for genetic improvement in cotton.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"10 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arabidopsis Nuclear Architecture related 1 facilitates the floral transition in a process involving molecular hydrogen","authors":"Pengfei Cheng, Yueqiao Wang, Ke Jiang, Chenxu Cai, Jun Wang, Yingying Zhang, Longna Li, Liqin Huang, Yan Zeng, Didier Pathier, Xu Cheng, Weiti Cui, Wenbiao Shen","doi":"10.1016/j.jare.2026.04.047","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.047","url":null,"abstract":"<h3>Introduction</h3>Although emerging evidence revealed that molecular hydrogen (H₂) positively regulates numerous physiological responses, understanding the synthesis of H₂ and its functions is a challenge for biology.<h3>Objectives</h3>The correct timing of flowering is controlled by environmental stimuli and endogenous signals. We report that endogenous H₂ facilitates the floral transition in Arabidopsis.<h3>Methods</h3>The Nuclear Architecture Related 1 (NAR1) gene of <em>Arabidopsis</em> was prokaryotic expressed and purified, and its H₂-synthesizing activity was subsequently detected. Furthermore, mutation experiments were used to investigate the catalytic roles of conserved sequences and Cys sites. Biochemistry and molecular approaches were employed to investigate the role of H₂ in regulating floral transition.<h3>Results</h3>Similar to [Fe-Fe] hydrogenase (HYD1) from <em>Chlamydomonas reinhardtii</em>, NAR1 protein is a H₂-synthesizing enzyme in <em>Arabidopsis thaliana</em>. Protein mutation experiments in vitro show that four Cys residues are important for the inducible catalyzing activity upon hypoxia. Accordingly, NAR1-dependent circadian-rhythmic H₂ was observed under light/dark cycles, which was accompanied with contrasting changes in nitric oxide (NO) signal. Knockdown of <em>NAR1</em> by CRISPR or RNAi reduced H₂ production and delayed flowering. Whereas, exogenous H₂ supply and overexpressing <em>NAR1</em> or <em>CrHYD1</em> promoted early flowering. These early flowering phenotypes were aggravated by the removal of endogenous NO, but abolished by NO addition. Since the mutant (<em>mms19</em>) defective in Fe-S cluster assembly function displays early flowering regardless of H₂ addition, we further deduce that NAR1 control of early flowering is largely achieved by H₂.<h3>Conclusion</h3>Biochemical and genetic evidences show that NAR1-driven floral transition is functionally linked to the modulation of circadian oscillators via NO signaling. Since H₂ production is modulated by circadian rhythms and constitutively produced, it may integrate external and internal cues into floral transition, and the modulation of its production might be a promising strategy for crop breeding cultivation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"70 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147708668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular adaptation of sweet potato to Martian soil simulant: insights from mRNA and long non-coding RNA analyses","authors":"Subramanyam Reddy Chinreddy, Karthik Chinnannan, Purushothaman Natarajan, Vaibhavi Patel, Gwonjin Lee, Manohar Chakrabarti, Padma Nimmakayala, Umesh K. Reddy","doi":"10.1016/j.jare.2026.04.050","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.050","url":null,"abstract":"<h3>Introduction</h3>Understanding how crops adapt to extraterrestrial environments is essential for sustainable space agriculture. Sweet potato (<em>Ipomoea batatas</em>), a nutritionally rich and stress-resilient crop, is a promising candidate for cultivation under Martian-like conditions, characterized by high salinity, heavy metal contamination, and poor water retention.<h3>Objective</h3>This study aimed to elucidate the molecular mechanisms underlying sweet potato adaptation to Martian soil analog conditions using Mars Global Simulant-1 (MGS-1).<h3>Methods</h3>Leaf, shoot, and storage root tissues of sweet potato grown in MGS-1 were subjected to RNA sequencing. Differentially expressed mRNAs and long non-coding RNAs (lncRNAs) were identified, and functional enrichment analyses were performed. Predicted <em>trans</em>-acting candidate lncRNAs were validated via virus-induced gene silencing (VIGS), with transcript levels confirmed by RT-qPCR.<h3>Results</h3>Transcriptome profiling revealed 2,344 differentially expressed mRNAs and 172 lncRNAs, enriched in abiotic stress-related pathways including secondary metabolite biosynthesis, ROS detoxification, zeatin biosynthesis, cell wall remodeling, and membrane transport. Several lncRNAs were predicted to regulate stress-responsive genes, including <em>Kunitz trypsin inhibitors</em>, <em>myo-inositol oxygenase</em>, <em>cytochrome P450s</em>, and <em>WRKY transcription factors</em>. Notably, MSTRG.1111.1 and MSTRG.5653.1 were identified as <em>trans</em>-acting regulators of <em>myo-inositol oxygenase</em> and <em>Kunitz trypsin inhibitor</em> genes, respectively. VIGS and RT-qPCR confirmed their regulatory roles, with transcript downregulation ranging from 0.5- to 2.8-fold.<h3>Conclusion</h3>This study provides the first comprehensive mRNA and lncRNA expression atlas of sweet potato under Martian soil analog conditions. The findings reveal key molecular pathways and lncRNA-mediated regulatory mechanisms for abiotic stress adaptation, highlighting sweet potato’s potential as a resilient crop for future space agriculture.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"47 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The commensal microbiome in respiratory tract tumors: From oncogenic mechanisms to clinical translation","authors":"Jiale Yu, Ciliang Guo, Yan Liu, Xuanqi Ren, Yibo Guo, Beibei Ran, Lingjun Xiao, Lingkai Kong, Xiaosong Gu, Chunping Jiang, Junhua Wu","doi":"10.1016/j.jare.2026.04.044","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.044","url":null,"abstract":"<h3>Background</h3>The human commensal microbiome, commonly recognized as a “second genome”, exerts a crucial regulatory role in host metabolism, immune homeostasis maintenance, and the progression of various diseases. Respiratory tract tumors remain a leading cause of global cancer-related deaths due to their high invasiveness and late-stage diagnosis. With the rapid development of high-throughput sequencing technology, the complex associations between microbial communities and respiratory tract tumors have been gradually uncovered. In lung cancer, distinct microbiota-related signatures, including tissue-specific and microbiota-derived ones have been identified, showing variations across cancer subtypes, anatomical sample sources, and patient demographics. These findings collectively lay the foundation for in-depth investigations into the interplay between the microbiome and respiratory tract tumors.<h3>Aim of review</h3>This review aims to systematically synthesize the current understanding of the commensal microbiome across respiratory tract tumors, primarily taking lung cancer as the main example, with systematic extensions to other respiratory tract malignancies, including laryngeal carcinoma and nasopharyngeal carcinoma, focusing on clarifying the ecological characteristics of microorganisms, elucidating the mechanistic links between the microbiome and tumorigenesis as well as progression, and summarizing the translational value of the microbiome in clinical practice, including applications in diagnostics, therapeutics, and prognostic evaluation.<h3>Key scientific concepts of review</h3>Emerging evidence highlights that the microbiome contributes to the initiation of respiratory tract tumors through multiple pathways: dysbiosis-induced chronic inflammation, immune system dysregulation, and metabolite-mediated epigenetic or functional alterations. Beyond tumorigenesis, the microbiome also plays a vital role in modulating the efficacy of cancer treatments, particularly conventional therapies and immunotherapies. Additionally, the microbiome provides novel opportunities for the development of diagnostic biomarkers and microbiome-targeted intervention strategies. Its prognostic potential in predicting recurrence, metastasis, and survival is increasingly recognized. These core scientific concepts collectively constitute the theoretical framework for exploring the microbiome’s role in respiratory tract tumor research and clinical translation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"32 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147696143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet factors 4 produces an antidepressant effect in mice via inhibition of neuroinflammation","authors":"Yi-Heng Li, Jin-Qiong Zhan, Ying Zhao, Zi-Ying Ouyang, Ling-Qing Luo, Bo Wei, Yuan-Jian Yang","doi":"10.1016/j.jare.2026.04.037","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.037","url":null,"abstract":"<h3>Introduction</h3>Platelet factor 4 (PF4) is secreted by platelets and can cross blood–brain barrier (BBB) to affect brain function, including regulations of neuroinflammation and synaptic plasticity, which are involved in the pathophysiology of depression. Nevertheless, whether PF4 participates in the development of depression has yet to be determined.<h3>Objectives</h3>The aim of this study was to investigate the role and the underlying mechanisms of PF4 in the pathophysiology of depression.<h3>Methods</h3>Mouse models of depression were established using chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) paradigms. Plasma levels of PF4 and inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). A battery of behavioral tests were conducted to evaluate the effects of systemic and intra-nucleus accumbens (NAc) administration of PF4 siRNA or PF4 on depressive-like behaviors. RNA sequencing (RNA-seq) for transcriptomic analysis and immunofluorescence staining were performed to assess neuroinflammatory status and microglial activation.<h3>Results</h3>Plasma PF4 was significantly reduced in patients with major depression. Similarly, CSDS mice exhibited decreased PF4 levels in both plasma and the NAc. Systemic PF4 administration produced an antidepressant-like effect in naive mice and rescued depressive-like behaviors in both CSDS and LPS-treated mice. In CSDS mice, intravenous administration of PF4 suppressed peripheral inflammatory response and increased PF4 levels in the NAc. Knockdown of PF4 in the NAc induced depressive-like behaviors in mice and markedly elevated inflammatory levels in this region. Correspondingly, infusion of PF4 into the NAc mitigated neuroinflammation, inhibited microglial activation, and alleviated depressive-like behaviors in CSDS mice. RNA-seq analysis also confirmed the suppressive effect of PF4 on neuroinflammatory pathways in the NAc.<h3>Conclusion</h3>Our findings demonstrate that PF4 exert an antidepressant effect, at least in part, by suppressing neuroinflammatory responses within the NAc. This work identifies PF4 as a novel and promising therapeutic target for the treatment of major depression.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"22 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuin 7-mediated deacetylation of hypoxia-inducible factor 1-alpha facilitates glycolytic reprogramming and inflammation of keratinocytes in psoriasis","authors":"Yixin Luo, Xiaolei Su, Chen Zhang, Zhenhua Liu, Kang Li, Pei Qiao, Chencan Su, Chunying Xiao, Xia Li, Jiaoling Chen, Lei Wang, Weinan Guo, Erle Dang, Gang Wang, Bing Li","doi":"10.1016/j.jare.2026.04.039","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.039","url":null,"abstract":"Psoriasis is a chronic inflammatory disease characterized by epidermal hyperplasia and dermal T cell infiltration. Epidermal keratinocytes function not only as the primary targets of the inflammatory response but also play a pivotal role in initiating and maintaining the inflammatory state. Sirtuin 7 (SIRT7), an NAD<ce:sup loc=\"post\">+</ce:sup>-dependent protein deacetylase, is critical for various cellular processes, including proliferation, metabolic homeostasis, and inflammation. However, its role in psoriasis remains elusive.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"5 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147681401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oligofructose alleviates hyperandrogenism in polycystic ovary syndrome through gut microbiota-derived bile acids","authors":"Yuhui Wang, Xitong Liu, Zhi Li, Ahui Kang, Yixuan Bai, Yang Wang, Yan Liu, Chujun Zhang, Jiaqi Yang, Qingqing Cai, Yi Feng, Huan Yi, Mengyu Zhang, Feifei Zhang, Haiou Liu, Congjian Xu","doi":"10.1016/j.jare.2026.04.036","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.036","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-age women, characterized by hyperandrogenism and metabolic dysfunction. Dietary interventions are recommended as one of the first-line therapies. Oligofructose (OFS), a prebiotic fiber, has demonstrated clinical benefits in PCOS; however, its underlying mechanism remains unclear.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"52 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147681386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Portulaca oleracea L. polysaccharide alleviates colitis-associated bone loss through Muribaculaceae-enriched gut microbiota and elevated colonic melatonin","authors":"Kun Li, Ruiqing Zhu, Yabo Chen, Xunkang Wang, Yiping Jiang, Ting Han, Xiaoqiang Yue, Tianshuang Xia, Hailiang Xin","doi":"10.1016/j.jare.2026.04.033","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.033","url":null,"abstract":"Colitis and its associated bone loss are major global health concerns with limited therapeutic options. <ce:italic>Portulaca oleracea</ce:italic> L. polysaccharide (POP) has been suggested to ameliorate both conditions via microbiota modulation. The study aimed to explore whether POP can alleviate colitis-associated bone loss and its underling mechanism.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"316 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147681544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ca2+ enhances the activity of prodelphinidin B digallate in lowering postprandial hyperglycemia via regulating the mucus layer","authors":"Yi Wang, Laiming Zhang, Jiaxiong Wu, Ziyang Deng, Yunxuan Li, Xingqian Ye, Haibo Pan, Shiguo Chen","doi":"10.1016/j.jare.2026.04.031","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.031","url":null,"abstract":"<h3>Introduction</h3>Phenolic compounds are regarded as promising α-glucosidase inhibitors for regulating postprandial blood glucose, but their α-glucosidase inhibitory activity <em>in vivo</em> is much lower than that <em>in vitro</em>. The small intestinal mucus layer serves as a barrier that impedes the binding of phenolic compounds to α-glucosidase, thereby attenuating their activity <em>in vivo</em>, yet the solution to this bottleneck remains unclear.<h3>Objectives</h3>Selecting prodelphinidin B digallate (proDB DG) as a representative phenolic compound, this study aimed to enhance its <em>in vivo</em> α-glucosidase inhibitory activity by screening the compound that can pre-regulate the barrier properties of the mucus layer.<h3>Methods</h3>The Caco-2/HT29-MTX-E12 co-culture model was used to screen the compound that can enhance the α-glucosidase inhibitory activity of proDB DG <em>in vivo</em>. This enhanced mechanism was analyzed using ultraviolet–visible light spectroscopy, zeta potential, rheological behavior, transmission electron microscopy, molecular dynamics simulation and Transwell mucus diffusion model. The improved α-glucosidase inhibitory activity and its biosafety were further confirmed by animal experiments. Moreover, the screened compound and proDB DG based tablets were developed.<h3>Results</h3>Ca²⁺ improved the activity of proDB DG in lowering postprandial hyperglycemia <em>in vivo</em>. This enhancement of activity is attributed to its pre-regulation on the barrier properties of the mucus layer. Specifically, Ca²⁺-derived mucin aggregation increased the porosity and diffusivity of the mucus layer, thereby improving the permeability of proDB DG and facilitating its binding to α‑glucosidase. Ca²⁺ also competitively bound with the mucus layer, and weakened the interaction between proDB DG and mucins. Furthermore, Ca²⁺–proDB DG based tablets possessed significant hypoglycemic effect and biosafety <em>in vivo</em>.<h3>Conclusion</h3>Ca²⁺ regulates the barrier properties of the mucus layer, thereby promoting proDB DG to reach the mucosa quickly and then interact with α-glucosidase effectively, which may break the application limitations of proDB DG and even phenolic compounds as α-glucosidase inhibitors clinically.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"3 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147666839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A “DUBTAC” targeting GLUL deubiquitination promotes BMSC osteogenic differentiation and implant osseointegration in type 2 diabetes","authors":"Lingxiao Wang, Zhanqiu Diao, Wanqing Wang, Yishu Huang, Yang Liu, Zhenhua Gao, Pan Ma, Zhaochen Shan, Jun Li, Zhipeng Fan","doi":"10.1016/j.jare.2026.04.034","DOIUrl":"https://doi.org/10.1016/j.jare.2026.04.034","url":null,"abstract":"<h3>Introduction</h3>Osseointegration in patients with type 2 diabetes mellitus (T2DM) is poor, and overcoming osseointegration impairment safely and efficiently remains challenging.<h3>Objectives</h3>To investigate the effect and process of GLUL on the osteogenic differentiation and osseointegration in T2DM by using BMSCs.<h3>Methods</h3>Human BMSCs were used for osteogenic differentiation in vitro and vivo, while C57BL/6 mice and GK male rats were used for in vivo osseointegration study. Cell transfection, western blotting, coimmunoprecipitation test, microscopic thermography, transcriptome sequencing and bioinformatic analysis favored in discovery of potential target protein and specific sites.<h3>Results</h3>The expression of glutamine synthetase (GLUL) is downregulated in the jawbone-derived BMSCs of T2DM patients. In this study, we found that GLUL protein homeostasis is important for the osteogenic differentiation of BMSCs and implant osseointegration. Synovial cell apoptosis inhibitor 1 (SYVN1) mediates the ubiquitination of GLUL protein at K259/334A, reducing GLUL protein expression and affecting the osteogenic differentiation of BMSCs. On this basis, we developed a GLUL-DUBTAC called HY-X3369, which is linked by the GLUL ligand HY-126351 and the covalent ligand of the deubiquitinase OTUB1 to target the GLUL ubiquitination site and reduce GLUL ubiquitination. Through pathway degradation, HY-X3369 maintains the protein homeostasis of GLUL in T2DM. HY-X3369 promotes the osteogenic differentiation of jawbone BMSCs from T2DM patients and inhibits GLUL degradation. In vivo evaluation further confirmed that HY-X3369 promotes osseointegration in GK rats.<h3>Conclusions</h3>This study reveals a promising strategy involving HY-X3369 to promote the function of BMSCs and osseointegration in T2DM, providing a theoretical basis and candidate methods for improving osseointegration in T2DM patients.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"3 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147666840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}