{"title":"Hypoxia inhibits intervertebral disc degeneration by maintaining autophagy circadian rhythm via the HIF1α-PER2-mTOR pathway","authors":"Guang-Cheng Yuan, Qi-Chen Zhang, Yu-Xiang Ge, Heng-Jie Zeng, Tai-Wei Zhang, Wang Ding, Zhi-Rui Dong, Yu-Kai Huang, Jian Dong, Nong Chen, Li-Bo Jiang","doi":"10.1016/j.jare.2025.12.036","DOIUrl":"10.1016/j.jare.2025.12.036","url":null,"abstract":"<div><h3>Introduction</h3><div>Disruption of the circadian rhythm (CR) and autophagy in intervertebral discs contributes to intervertebral disc degeneration (IDD) progression. However, the circadian regulation of autophagy requires further investigation.</div></div><div><h3>Objectives</h3><div>We observed the expression of circadian proteins and autophagic markers of nucleus pulposus (NP) cells followed a diurnal rhythmic pattern in vivo and in vitro.</div></div><div><h3>Methods</h3><div>NP tissues were collected from light/dark cycle–shifted rats and IDD patients of varying severity. CR and ECM-related proteins were analyzed by immunohistochemistry and western blotting. Primary rat NP cells were treated with hypoxia or CoCl<sub>2</sub>, followed by western blotting for CR proteins, HIF-1α, and autophagy markers. siRNA knockdown of PER2 or HIF-1α was performed to assess their roles in regulating autophagy, ECM, and CR-associated proteins.</div></div><div><h3>Results</h3><div>The silencing of clock gene PER2 disrupted the rhythmic expression of autophagic markers, by contrast PER2 overexpression inhibited mTOR pathway and enhanced autophagic levels. Co-IP analysis demonstrated the PER2-mTOR interaction, linking CR and autophagy rhythm. The inflammatory stimulator dampened the CR and autophagy rhythm, however intermittent hypoxia and cobalt chloride (CoCl<sub>2</sub>) re-synchronized the rhythm. Mechanistically, HIF-1α-mediated regulation of PER2 by hypoxia was involved in the re-synchronization, which was further demonstrated by the loss of CR and autophagy rhythm after silencing of PER2 or HIF-1α under hypoxia. Furthermore, the rhythm of oxygen level and HIF-1α was proved in living healthy NP tissue, confirming the hypoxia as a Zeitgeber. CR disruption and autophagy dysfunction led to catabolism of extracellular matrix (ECM), but the hypoxia, CoCl<sub>2</sub> and autophagic stimulator could promote the rebalance of ECM metabolism.</div></div><div><h3>Conclusion</h3><div>Our study demonstrates that hypoxia maintains the intrinsic CR and autophagy rhythm through the HIF-1α/PER2/mTOR pathway to prevent IDD.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 759-774"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Time-series transcriptome and metabolome profiling Uncovers WRKY6 and WRKY23 as critical regulators in tobacco response to Pseudomonas syringae infection","authors":"Xinhua Tian, Peng Lu, Zechao Qu, Huan Su, Qiao Wang, Jiemeng Tao, Qian Sun, Shuaibin Wang, Lijun Meng, Peijian Cao, Yuanhu Xuan, Jingjing Jin","doi":"10.1016/j.jare.2026.01.036","DOIUrl":"10.1016/j.jare.2026.01.036","url":null,"abstract":"<div><h3>Introduction</h3><div><em>Pseudomonas syringae</em> pv. <em>tabaci</em>, a Gram-negative bacterial pathogen, causes devastating tobacco wildfire disease with global economic impacts. While its pathogenicity is well documented, the dynamic defense mechanisms of tobacco against infection remain poorly understood.</div></div><div><h3>Objective</h3><div>This study aimed to decipher phased defense mechanisms of tobacco against <em>P. syringae</em> infection through multi-omics integration, with emphasis on elucidating spatiotemporal coordination between transcriptional reprogramming and metabolic remodeling, and functionally validating critical regulatory modules.</div></div><div><h3>Methods</h3><div>Time-series transcriptomic and metabolomic profiling was integrated to reconstruct dynamic response patterns. Stage-specific regulatory modules were explored via TO-GCN and WGCNA, and the roles of <em>WRKY6</em> and <em>WRKY23</em> in disease resistance were validated by generating transgenic lines.</div></div><div><h3>Results</h3><div>Early infection (12–24 hpi) prioritized stress signaling and hormone pathway activation (salicylic acid/jasmonate), transitioning to cellular homeostasis regulation at late stages (48–60 hpi). WRKY, ERF, and NAC families orchestrated stage-specific gene expression. Notably, <em>WRKY6</em> and <em>WRKY23</em> functioned as negative regulators, with their silencing leading to a reduction in lesion area by 42–58% and pathogen load by 3.2–4.5 fold. Metabolomic analysis revealed sustained activation of phenylpropanoid metabolism, specifically regulating L-phenylalanine homeostasis and biosynthesis of its defense derivative xanthosine. Additionally, core modules involved in sphingolipid metabolism, light responses, and hormone cross-talk were also identified.</div></div><div><h3>Conclusion</h3><div>We demonstrate that WRKY-mediated transcriptional reprogramming coordinates phytohormone signaling, sphingolipid dynamics, and light responses to spatiotemporally regulate secondary metabolite production. The identified <em>WRKY6</em> and <em>WRKY23</em> regulatory module establishes a molecular framework for engineering disease resistance, and the proposed two-phase defense model (early signaling → late metabolic remodeling) advances understanding of plant–pathogen interactions and offers targets for precision breeding.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 117-133"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Regenerated lignocellulosic material from pea, bean, and artichoke waste as feedstock for bioplastic production","authors":"Cyrine Amara, Safa Baraketi, Yosr Barchouchi, Yassine M’Rabet, Wiem Ayadi, Mabrouk Horchani, Khaoula Khwaldia","doi":"10.1016/j.jare.2026.01.056","DOIUrl":"10.1016/j.jare.2026.01.056","url":null,"abstract":"<div><h3>Introduction</h3><div>Vegetable processing generates large quantities of lignocellulosic waste that are often underutilized. Developing bioactive, biodegradable packaging materials from such residues aligns with circular bioeconomy goals. This study explores oxalic acid-choline chloride deep eutectic solvent (DES) fractionation as a green approach to valorize artichoke bracts, pea pods, and bean pods into high-performance lignocellulosic bioplastics.</div></div><div><h3>Objectives</h3><div>The aim was to regenerate lignocellulosic matrices in situ and fabricate bioplastics with tailored structure–property relationships, while providing mechanistic insights into the molecular interactions governing their performance.</div></div><div><h3>Methods</h3><div>Raw wastes were subjected to DES fractionation, which selectively reorganized cellulose, depolymerized hemicellulose, and regenerated lignin. Fourier-transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) were used to confirm structural changes. Mechanical, barrier, thermal, antioxidant, antimicrobial, and biodegradation properties were evaluated. Molecular docking simulations were performed to investigate lignin-cellulose interactions.</div></div><div><h3>Results</h3><div>DES treatment produced dense fibrillar networks in artichoke-derived bioplastics and more porous architectures in pea and bean pod bioplastics. Molecular docking indicated favorable lignin-cellulose interactions (binding energies − 4.9 to − 5.2 kcal/mol) stabilized by oxalic acid-mediated hydrogen bonds, supporting enhanced matrix cohesion. Artichoke bract bioplastics exhibited the highest tensile strength (7.02±0.68 MPa) and Young’s modulus (428.11±44.47 MPa), whereas bean pod bioplastics achieved the highest elongation at break (8.35±1.30 %). Pea pod bioplastics offered superior water vapor barrier properties. Thermal stability was enhanced (T<sub>d</sub> = 244–266 °C), UV–Vis light transmittance was below 2 %, and the films retained antioxidant and antimicrobial activity. Soil burial tests showed 56–69 % mass loss within 70 days, indicating rapid biodegradability.</div></div><div><h3>Conclusion</h3><div>This work demonstrates that DES-mediated regeneration of lignocellulosic material is an effective strategy to produce multifunctional, bioactive, and environmentally degradable bioplastics. By correlating molecular-level lignin-cellulose interactions with macroscopic mechanical, barrier, and bioactive properties, the study provides mechanistic insight and practical guidance for the rational design of sustainable packaging materials within a circular bioeconomy framework.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 149-164"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comparative genomics reveals two major lineages of Bifidobacterium adolescentis in the human gut, driven by divergent adaptation in China and the United States","authors":"Linbo Shi, Meng Zhang, Ruonan Zheng, Lai-Yu Kwok, Wenyi Zhang","doi":"10.1016/j.jare.2026.01.071","DOIUrl":"10.1016/j.jare.2026.01.071","url":null,"abstract":"<div><h3>Introduction</h3><div><em>Bifidobacterium adolescentis</em> is a key beneficial member of the human gut microbiota, but its genomic diversity and evolutionary drivers across human populations remain poorly characterized.</div></div><div><h3>Objectives</h3><div>Understanding genomic functional heterogeneity and evolutionary patterns in human gut-derived <em>B. adolescentis</em>.</div></div><div><h3>Methods</h3><div>We performed a comparative genomic analysis of 395 <em>B. adolescentis</em>, mainly from China (<em>n</em> = 169) and the United States (<em>n</em> = 146), with smaller sets from Australia, Italy, and the United Kingdom, to investigate functional heterogeneity and evolutionary mechanisms. Our analysis integrated core and pan-genome architecture, phylogenomics, single nucleotide polymorphism (SNP)-based population structure, carbohydrate-active enzyme profiles, CRISPR-Cas systems, antibiotic resistance genes, and recombination dynamics.</div></div><div><h3>Results</h3><div>The pan-genome was open and highly plastic. Phylogenetic reconstruction identified two major clades with strong geographic stratification: Chinese isolates predominantly clustered in Clade B, while U.S. isolates grouped in Clade A. Functional annotation showed regional specialization in carbohydrate-active enzymes, with Chinese isolates enriched in glycosyltransferase families and U.S. isolates in carbohydrate-binding module and carboxylesterase families, likely reflecting dietary adaptations. Genomic islands were hotspots for horizontal gene transfer, harboring region-specific carbohydrate-active enzymes and antibiotic resistance genes such as <em>tet(W/32/O)</em> and <em>ermX</em>, which were frequently located in Chinese isolates. Recombination was found to be the primary driver of genetic diversity, with recombination-to-mutation ratios approaching and exceeding 3.0 in Chinese and U.S. isolates. Linkage disequilibrium decay further supported higher recombination rates in these populations.</div></div><div><h3>Conclusion</h3><div><em>B. adolescentis</em> has diverged into two major genomic lineages, primarily associated with isolates from China and the U.S. This divergence reflects adaptation to distinct host-associated ecological factors, such as diet, antibiotic exposure, and lifestyle, and is predominantly driven by extensive homologous recombination rather than point mutations. These findings highlight how regional selective pressures shape the genomic and functional landscape of this key gut symbiont.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 611-624"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Astrocyte-derived LAMC1 protects against intracerebral hemorrhage: A novel genetic mechanism maintaining neurovascular integrity","authors":"Liang Cao, Yanjun Zhang, Wenjun Pi, Rui Zhang, Yi Zhang, V.Wee Yong, Mengzhou Xue","doi":"10.1016/j.jare.2026.01.028","DOIUrl":"10.1016/j.jare.2026.01.028","url":null,"abstract":"<div><h3>Introduction</h3><div>Intracerebral hemorrhage (ICH) is a devastating stroke subtype, yet the intrinsic mechanisms conferring genetic protection against it remain poorly understood. While risk-associated loci have been identified, the cell-type-specific pathways that actively preserve cerebrovascular stability remain largely unmapped.</div></div><div><h3>Objectives</h3><div>This study aimed to bridge the critical gap in understanding cell-type-specific mechanisms of ICH by identifying novel protective genetic drivers essential for maintaining neurovascular integrity, utilizing an integrative multi-omics approach.</div></div><div><h3>Methods</h3><div>We integrated large-scale human genetic data with multi-omics approaches (TWAS, PWAS) and single-cell analysis to identify cell-type-specific risk genes for ICH. We validated our core findings using a collagenase-induced mouse model of ICH. To definitively establish causality, we further conducted in vivo gain-of-function studies via <em>retro</em>-orbital injection of adeno-associated virus (AAV) vectors. By combining Evans Blue extravasation assays, brain edema measurements, and neurobehavioral testing, we systematically evaluated the impact of LAMC1 on blood–brain barrier (BBB) integrity and neurological functional outcomes.</div></div><div><h3>Results</h3><div>Multi-omics analysis indicated that genetically determined reduced LAMC1 expression increases ICH risk, with single-cell eQTL pinpointing astrocytes as key drivers. In vivo, LAMC1 was downregulated in astrocytes and endothelial cells post-ICH. Crucially, LAMC1 overexpression attenuated brain edema and tissue necrosis, markedly improving neuromotor function. Mechanistically, LAMC1 preserved BBB integrity by inhibiting the degradation of the tight junction proteins ZO-1 and occludin.</div></div><div><h3>Conclusion</h3><div>This study not only identifies astrocyte-derived LAMC1 as a “vascular guardian” essential for maintaining neurovascular unit integrity, but also provides definitive causal evidence via gain-of-function experiments that elevating LAMC1 levels effectively stabilizes the blood–brain barrier and improves ICH outcomes. Consequently, this establishes LAMC1 as a critical target for precision intervention aimed at enhancing vascular resilience and for the prevention and treatment of ICH.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 867-884"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pan-cancer epigenetic landscape of human tumor-associated macrophages reveals crucial enhancers governing their heterogenous formation by Pol II pausing modulation","authors":"Chenchen Xiong, Hanhan Ning, Xiaoqiang Wang, Yushuang Xie, Zeyu Liu, Deqing Hu, Xin Gao","doi":"10.1016/j.jare.2026.01.048","DOIUrl":"10.1016/j.jare.2026.01.048","url":null,"abstract":"<div><h3>Introduction</h3><div>Tumor-associated macrophages (TAMs) are a functionally heterogeneous population within the tumor microenvironments, exhibiting both anti-tumor and pro-tumor functions. Pro-tumorigenic TAMs can derive from peripheral monocytes or tissue-resident macrophages (TRMs). However, the epigenetic mechanisms driving the differentiation of these distinct cellular sources into specific TAM subtypes remain unclear.</div></div><div><h3>Objectives</h3><div>Here, we sought to define the epigenetic mechanisms that drive the divergent differentiation of monocyte and TRM-derived TAMs. Through a pan-cancer analysis, we map the regulatory cascade, from <em>cis</em>-regulatory elements and key transcription factors to the release of RNA Polymerase II (Pol II) pausing, that specifies TAM heterogeneity.</div></div><div><h3>Methods</h3><div>We performed single-cell epigenetic profiling of macrophages derived from various human cancers, precancerous lesions, and healthy adult and fetal tissues using publicly available datasets, coupled with single-cell multi-omics integration. Key findings were validated through multi-omics analysis of mouse bone marrow-derived macrophage and CRISPR-based functional assays using in vitro human cell culture models.</div></div><div><h3>Results</h3><div>We delineated the distinct epigenetic developmental trajectories by which peripheral monocytes and TRMs give rise to SPP1+ and C1QC + TAM, respectively. Along the monocyte-to-SPP1<sup>+</sup> TAM trajectories, we identified PPARG, NFAT5 and MECP2 as pivotal regulators that promote pro-tumorigenic polarization. Conversely, the differentiation of TRMs to C1QC + TAMs was associated with regulators MAF, HES1 and PRDM1. Furthermore, we discovered a core transcriptional signature regulated by SPP1+ TAM-specific super-enhancers that is significantly associated with poor prognosis across 18 cancer types. Mechanistically, we demonstrated that these enhancers, such as HIPK2 enhancers, establish the pro-tumorigenic TAM state primarily by modulating Pol II pausing rather than by altering promoter accessibility of their target genes.</div></div><div><h3>Conclusion</h3><div>Our work delineates the epigenetic and transcriptional circuitry that establishes TAM heterogeneity as potential therapeutic levers to enhance cancer immunotherapy.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 929-945"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145995509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhiguang Qu, Deng Chen, Hong Hu, Hao Liu, Lu Zheng, Junbin Huang, Yunfeng Li, Lida Zhu, Xiaolin Chen
{"title":"Selectively targeting UDP-glucose 4-epimerase MoUGE1 for controlling rice blast disease","authors":"Zhiguang Qu, Deng Chen, Hong Hu, Hao Liu, Lu Zheng, Junbin Huang, Yunfeng Li, Lida Zhu, Xiaolin Chen","doi":"10.1016/j.jare.2026.01.072","DOIUrl":"10.1016/j.jare.2026.01.072","url":null,"abstract":"<div><h3>Introduction</h3><div>The fungal cell wall, a dynamic structure critical for pathogenesis, is composed of polysaccharides and proteins. UDP-glucose 4-epimerases (UGEs) play a pivotal role in cell wall synthesis by converting UDP-galactose between UDP-glucose. This study investigates the role of MoUGE1 in <em>Magnaporthe oryzae</em> pathogenesis and explores its potential as an antifungal target for fungal disease control. A lead inhibitor targeting MoUGE1 was identified through virtual screening.</div></div><div><h3>Objectives</h3><div>The aims of this study were to elucidate the role of MoUGE1 in <em>M. oryzae</em> during rice blast pathogenesis, assess its potential as an antifungal target, and identify potential MoUGE1 inhibitors through virtual screening to control rice blast.</div></div><div><h3>Methods</h3><div>To analyses the role of MoUGE1 in <em>M. oryzae</em>, we generated Δ<em>uge1</em> mutants via split-PCR-mediated gene knockout. The impact of <em>MoUGE1</em> on fungal growth, cell wall composition, and plant infection was assessed. Metabolomic analysis revealed the impact of <em>MoUGE1</em> deletion on metabolic processes of rice blast. Structure-based virtual screening, molecular dynamics (MD) simulation and surface plasmon resonance (SPR) used to find hit compounds inhibiting MoUGE1.</div></div><div><h3>Results</h3><div>The Δ<em>uge1</em> exhibited reduced mycelial growth, altered cell wall and cell membrane composition, and impaired plant infection. Metabolomic analysis and western blot revealed accumulation in UDP-galactose and alteration of N-glycosylation, leading to cell wall instability and increased sensitivity to cell wall stressors. Virtual screening identified lig122132 as a potential MoUGE1 inhibitor, which was further confirmed through MD simulation and SPR, showing stable binding to the MoUGE1.</div></div><div><h3>Conclusion</h3><div>Our findings emphasize the significance of <em>MoUGE1</em> in fungal cell wall integrity, appressorium function, and virulence in <em>M. oryzae</em>. Identifying MoUGE1 as a target for antifungal intervention provides new insights into the molecular mechanisms of rice blast pathogenesis and paves the way for developing innovative strategies against this major agricultural disease. The potential MoUGE1 inhibitor, lig122132, is a promising starting point for the development of novel fungicides to control rice blast.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 165-178"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lei Zhu,Yan Long,Jiaqi Han,Kun Ji,Jing Wu,Xiangyuan Wan
{"title":"Gravity-shaped plant architecture to enhance dense planting, lodging resistance and substance uptake and their applications in maize and other crop breeding","authors":"Lei Zhu,Yan Long,Jiaqi Han,Kun Ji,Jing Wu,Xiangyuan Wan","doi":"10.1016/j.jare.2026.10.004","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.004","url":null,"abstract":"","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"148 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090554","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}
Mingming Lu, Yanan Chu, Ziwei Zhu, Hong Zhou, Danfei Zhu, Siyi Chen, Congfan Bu, Qiheng Qian, Chen Gao, Meiye Jiang, Hao Zhang, Jinyue Wang, Jingyao Zeng, Zhewen Zhang, Qiong Zhao, Shuai Liu, Xudong Fu, Na Kong, Francis KM Chan, Yongcheng Wang, Xin Sheng
{"title":"Genotype-driven variations in lncRNA expression underlie predisposition to high-grade serous ovarian cancer","authors":"Mingming Lu, Yanan Chu, Ziwei Zhu, Hong Zhou, Danfei Zhu, Siyi Chen, Congfan Bu, Qiheng Qian, Chen Gao, Meiye Jiang, Hao Zhang, Jinyue Wang, Jingyao Zeng, Zhewen Zhang, Qiong Zhao, Shuai Liu, Xudong Fu, Na Kong, Francis KM Chan, Yongcheng Wang, Xin Sheng","doi":"10.1016/j.jare.2026.01.014","DOIUrl":"10.1016/j.jare.2026.01.014","url":null,"abstract":"<div><h3>Introduction</h3><div>New effective early diagnosis strategies and therapeutic targets are desperately needed for high-grade serous ovarian cancer (HGSOC). Previous functional interpretation of HGSOC genome-wide association studies (GWAS) have largely overlooked the role of long non-coding RNAs (lncRNAs).</div></div><div><h3>Objectives</h3><div>Our study aims to identify novel causal genes, particularly lncRNAs, that contribute to HGSOC susceptibility and to explore whether their may provide preliminary insights relevant to early detection or therapeutic development.</div></div><div><h3>Methods</h3><div>We mapped genotype effects on the expression of both protein-coding genes (PCGs) and lncRNAs in 348 HGSOC tumor samples. By performing Bayesian colocalization analysis, we prioritized causal genes in HGSOC tumors and whole blood, respectively. Next, we generated a single-nucleus full-length transcriptome map of HGSOC tumor using snRandom-seq. Furthermore, we conducted <em>in vitro</em> assays to validate the functional role of lncRNA <em>CRHR1-IT1</em> in HGSOC.</div></div><div><h3>Results</h3><div>Our findings reveal that genetic variants significantly drive expression changes in both PCGs and lncRNAs. Notably, lncRNAs contribute a greater proportion of HGSOC heritability than PCGs. Using Bayesian colocalization analysis, we prioritized 22 high-fidelity causal genes in HGSOC tumors and whole blood, including <em>ARL17A</em> and <em>CRHR1-IT1</em>. Through snRandom-seq, we characterized the single-cell expression patterns of candidate susceptibility PCGs and lncRNAs in HGSOC tumors. Furthermore, we showed that elevated <em>CRHR1-IT1</em> expression promotes apoptosis and inhibits the growth of HGSOC cells <em>in vitro</em>.</div></div><div><h3>Conclusion</h3><div>Our study highlights the significant regulatory role of genetic variants on both protein-coding genes and lncRNAs in HGSOC. While these findings enhance our understanding of HGSOC susceptibility and may inform future efforts toward biomarker discovery or immune-related therapeutic exploration.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 229-245"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}