Journal of advanced research最新文献

{"title":"A novel framework for identifying cellular signature LncRNAs and their functional coregulatory networks with prognostic implications at single-cell resolution.","authors":"Jing Bai, Xinyu Li, Congxue Hu, Chuo Peng, Jing Chen, Weixin Liang, Xia Li, Yunpeng Zhang","doi":"10.1016/j.jare.2026.10.034","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.034","url":null,"abstract":"<p><strong>Introduction: </strong>Long non-coding RNAs have been implicated in crucial roles in developing malignant tumors. However, comprehensive analyses of lncRNA within the tumor microenvironment, particularly at the single-cell level across various tumor types, remain limited.</p><p><strong>Objectives: </strong>This study aimed to establish a comprehensive methodological framework for prioritizing and identifying novel cancer-associated lncRNA biomarkers and potential therapeutic targets at the single-cell level, and to integrate these findings into a unified platform.</p><p><strong>Methods: </strong>We developed SIGLNCOS, a computational framework for analyzing single-cell lncRNA regulation via: i) Constructing the lncRNA visualization landscape. ii) Identifying cellular signature lncRNA. iii) Functional enrichment of clncRNAs. iv) Identifying co-lncRNA pairs based on shared functional annotations and weighted functional association scores. Cell-composition-adjusted prognostic analysis evaluated the prognostic relevance of individual lncRNAs and co-lncRNA pairs.</p><p><strong>Results: </strong>Applying SIGLNCOS, we identified 667 cellular-signature lncRNAs (clncRNAs) from over half a million single cells across 31 cancers, revealing their roles in immune modulation, tumor progression, and differentiation. NEAT1 was associated with distinct macrophage states and functional changes along pseudotime. SIGLNCOS identified 3,381 co-lncRNA pairs involved in key cancer-related pathways, revealing a complex landscape of lncRNA co-regulation. Notably, we uncovered distinct co-lncRNA networks associated with different thyroid cancer states, particularly between papillary thyroid carcinoma and anaplastic thyroid carcinoma. These networks exhibit functionally concordant regulatory effects that individual lncRNAs cannot, underscoring the importance of co-regulation in tumor evolution. The prognostic analysis demonstrated that co-lncRNA networks outperform individual lncRNAs in predicting patient outcomes, emphasizing their potential as biomarkers and therapeutic targets.</p><p><strong>Conclusion: </strong>This study constructs pan-cancer lncRNA landscapes and develops SIGLNCOS, a comprehensive framework for uncovering lncRNA at single-cell resolution, offering new insights into cancer biology and potential avenues for targeted therapies and novel biomarker discovery. We further developed sCo-Lnc (https://bio-bigdata.hrbmu.edu.cn/scolnc), a web-based platform for visualizing novel lncRNA biomarkers across cancers.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in research on the association between lactylation and regulated cell death in sepsis.","authors":"Leyu Ai, Huirong Wu, Wanyi Huang, Yang Zhang, Yuexiang Ma, Dan Wu, Jijun Chen, Xiaobing Fang, ChenXu Liu, Peiwen Wang, Wenjie Cheng, Heliang Fu, Wen Yin, Kuo Shen, Junjie Li","doi":"10.1016/j.jare.2026.10.026","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.026","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a life-threatening organ dysfunction mediated by host immune dysregulation, and elevated serum lactate levels are an important pathophysiological feature. Lactate is not only the terminal product of glucose metabolism but also acts as a signaling molecule that regulates gene expression and protein function through lactylation. Regulated cell death (RCD), as a targetable terminal cell fate, offers a potential direction for precision intervention in sepsis.</p><p><strong>Objective: </strong>Although studies have indicated that lactylation can affect sepsis progression by regulating RCD, no review has systematically summarized this relationship. Therefore, this review systematically summarizes the regulatory roles of lactylation in RCD and their pathological significance in sepsis.</p><p><strong>Innovation: </strong>Based on the above evidence, this review proposes that \"lactylation modification imbalance-aberrant activation of RCD\" may be a potential driving mechanism of sepsis progression and that the lactylation/acetylation imbalance caused by glucose metabolism reprogramming is an upstream regulatory link of this axis.</p><p><strong>Conclusion: </strong>In summary, targeting lactylation modification to precisely modulate RCD may interrupt the pathological chain from lactate elevation to organ injury, providing new perspectives for sepsis treatment research.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Longitudinal prediction of drug response in high-grade serous ovarian cancer organoid cultures aligning with clinical responses\" [J. Adv. Res. 83 (2026) 379-390].","authors":"Enrico Cavarzerani, Isabella Caligiuri, Michele Bartoletti, Giuseppe Corona, Tiziana Perin, Antonio Palumbo, Antonino Ditto, Tommaso Occhiali, Vincenzo Canzonieri, Flavio Rizzolio","doi":"10.1016/j.jare.2026.10.010","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.010","url":null,"abstract":"","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psyllid glycine-rich antimicrobial peptides oligomerize to directly cleave zinc transporter ZnuA on the membranes of citrus Huanglongbing pathogen.","authors":"Hongyan Peng, Yu Bin, You Li, Yu Du, Chuang Wang, Shuai Wang, Taiyun Wei","doi":"10.1016/j.jare.2026.10.012","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.012","url":null,"abstract":"<p><strong>Introduction: </strong>Huanglongbing (HLB), the most devastating citrus disease worldwide, is caused by Candidatus Liberibacter asiaticus (CLas) and transmitted by Asian citrus psyllid, Diaphorina citri. Currently, the potential role of the insect vector's innate immunity against CLas remains poorly understood.</p><p><strong>Objectives: </strong>This study aimed to identify and characterize a 41-amino acid glycine-rich antimicrobial peptide from D. citri (DcGrAMP1), elucidate its molecular mechanism against CLas and related α-proteobacteria, and evaluate its efficacy in suppressing CLas in HLB-affected citrus under greenhouse and field conditions.</p><p><strong>Methods: </strong>Through genomic screening and CLas-induced expression validation, we obtained DcGrAMP1; combined with structural prediction, site-directed mutagenesis, molecular interaction techniques, and RNA interference, we elucidated its mechanism against CLas and regulatory pathway; through transgenic citrus construction and protein injection assays, we validated its CLas-suppressive efficacy under greenhouse and field conditions.</p><p><strong>Results: </strong>DcGrAMP1 exhibits remarkable thermal stability. It oligomerizes through Arg26/Arg31 for bacterial membrane penetration, and Arg21 engages in binding-associated cleavage upon interacting with Asp153 of zinc transporter ZnuA on CLas membranes, thereby cleaving the adjacent peptide bond and triggering ZnuA degradation. CLas infection activates the c-Jun N-terminal kinase-activator protein 1 (JNK-AP1) signaling pathway in the psyllid, thereby upregulating DcGrAMP1 expression. Overexpression or injection of DcGrAMP1 in citrus significantly reduced CLas titers and alleviated HLB symptoms.</p><p><strong>Conclusion: </strong>This work provides the evidence that insect AMPs can oligomerize to penetrate CLas membranes, and then directly cleave zinc transporter ZnuA on the membranes of citrus Huanglongbing pathogen.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc peroxide-coated gold nanorods as the therapeutic adjuvants for photothermal enhanced chemodynamic therapy and metalloimmunotherapy against tumor.","authors":"Huixi Yi, Chao Jiang, Zheng-Yin Pan, Nannan Fu, Liyou Guo, Zhixiong Zhan, Jingyao Li, Xiaoya Zhao, Lingmin Zhang, Yue Zheng, Dong-Yang Zhang","doi":"10.1016/j.jare.2026.10.011","DOIUrl":"10.1016/j.jare.2026.10.011","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Traditional tumor therapies have limited efficacy, leading to a high mortality rate. Although immunotherapy holds considerable therapeutic promise, clinical immunotherapy for solid tumors only elicits durable responses in a minority of patients. This limitation is largely attributed to the highly immunosuppressive nature of the tumor microenvironment (TME). Notably, conventional chemodynamic therapy (CDT) is hampered by endogenous hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;) shortage in tumor cells, and AZP compensates this defect via in-situ H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; self-supplementation to amplify hydroxyl radical generation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;To develop a nanoplatform capable of systematically enhancing anti-tumor immunity, we rationally constructed a PEGylated zinc peroxide-coated gold nanorod (AZP) as a therapeutic adjuvant with acid-responsive properties for the combination therapy of cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Gold nanorod-based adjuvants coated with zinc peroxide were successfully prepared via chemical oxidation, followed by PEGylation. The morphology and size of the AZP were characterized using transmission electron microscopy (TEM) and hydrodynamic diameter measurements. The elemental composition of AZP was determined by X-ray photoelectron spectroscopy and energy-dispersive X-ray spectroscopy analysis. The acid-responsive degradation and photothermally enhanced catalytic properties of AZP were evaluated using TEM, inductively coupled plasma mass spectrometry, absorption spectroscopy, and thermal imaging tracing. The therapeutic mechanism of AZP at the cellular level was investigated through a series of experiments, including TEM, fluorescence imaging, immunofluorescence assays, Seahorse analysis, western blotting, and bioinformatics approaches, which comprehensively clarified the anti-tumor mechanism of AZP. Bilateral tumor and metastatic tumor models were established to verify the anti-tumor efficacy and mechanism of AZP at the animal level. Specifically, fluorescence imaging, immunofluorescence staining, tissue staining analysis, enzyme-linked immunosorbent assay, and flow cytometry were performed to assess the in vivo therapeutic effects.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In the acidic TME, the AZP nanoplatform releases H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; and zinc ions, which increases the reactive oxygen species level in cancer cells. Additionally, due to its photothermally enhanced peroxidase-like activity, AZP induces the generation of more hydroxyl radicals under light irradiation. These effects synergistically disrupt lysosomes and mitochondria in tumor cells, block autophagy, and ultimately lead to tumor cell death. Furthermore, zinc supplementation by AZP enhances the activation of the cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) pathway. Meanwhile, the combined treatment induces immunogenic cell death of cancer cells, which promotes the releas","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between dental pulp necroptosis-related signaling and elodont incisor growth retardation in hyperglycemic rats.","authors":"Min Guk Kim, Heithem Ben Amara, Peter Thomsen, Farah Asa'ad, Chan Ho Park","doi":"10.1016/j.jare.2026.10.027","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.027","url":null,"abstract":"<p><strong>Introduction: </strong>Although type 1 diabetes (T1D) induces systemic allostatic load, whether sustained hyperglycemia is accompanied by necroptosis-related signaling within the dental pulp (DP) niche and its impact on the developmental kinetics of continuously growing elodont incisors remains unclear.</p><p><strong>Objectives: </strong>This study investigated whether sustained hyperglycemia was accompanied by enhanced RIPK3-MLKL necroptosis-related signaling within the DP niche and whether these molecular alterations coincided with attenuation of elodont incisor growth.</p><p><strong>Methods: </strong>T1D was induced in Sprague-Dawley rats using streptozotocin (65 mg/kg). Systemic metabolic profiles, necroptotic markers in serum/dental tissues (immunohistochemistry, ELISA, and Western blotting), and mandibular incisor growth (a standardized notch-creation method for 49 days) were evaluated. Group differences were assessed primarily using two-sided Welch's t-tests, with exact Mann-Whitney U tests for sensitivity analyses, while discriminative performance was evaluated using receiver operating characteristic (ROC-AUC) and precision-recall (PR curve-based AP) analyses.</p><p><strong>Results: </strong>Hyperglycemic rats exhibited impaired weight gain, systemic inflammatory induction (elevated NLR/MLR), and elevated hepatic stress markers. Molecular profiling demonstrated increased oxidative damage (4-HNE) and necroptosis-related molecular alterations in dental tissues and DP-derived cells. Incisor growth rates differed significantly at the Phase-Transition (0.532 vs. 0.400 mm/day; Welch's p = 0.024), reaching definitive retardation in Phase-2 (0.594 vs. 0.408 mm/day; p < 0.001). Discriminatory performance improved from the Phase-Transition (ROC-AUC = 0.693; AP = 0.784) to Phase-2 (ROC-AUC = 1.000; AP = 1.000). Glycemic reversion was accompanied by normalization of necroptosis-related markers and incisor growth kinetics.</p><p><strong>Conclusion: </strong>Hyperglycemia-induced incisor growth retardation is associated with increased oxidative stress, altered PGAM5 expression, and enhanced RIPK3-MLKL necroptosis-related signaling in dental tissues and DP-derived cells. Translationally, longitudinal evaluation of elodont incisor growth kinetics could serve as a minimally invasive phenotypic indicator of metabolic dysregulation in preclinical diabetic models and support refinement under the 3Rs principle.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitophagy and ER-phagy in doxorubicin-induced cardiotoxicity: mechanisms, crosstalk, and therapeutic implications.","authors":"Yingjie Tian, An Chang, Zhijiang Guo, Hao Zhou, Xing Chang, Jie Wu","doi":"10.1016/j.jare.2026.10.022","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.022","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin (DOX) is a key chemotherapeutic agent for hematologic malignancies and many solid tumors, but its clinical use is limited by doxorubicin-induced cardiotoxicity (DIC). DIC may present as subclinical myocardial injury, arrhythmias, left ventricular dysfunction, cardiomyopathy, or heart failure. DOX can disrupt organelle function through topoisomerase IIβ (Top2β)-mediated DNA damage and transcriptional stress, oxidative stress, disrupted iron homeostasis, and calcium imbalance. Mitochondrial and endoplasmic/sarcoplasmic reticulum (ER/SR) injury are therefore central pathological features of DIC.</p><p><strong>Aim of review: </strong>This review summarizes current evidence on mitophagy and ER-phagy in DIC, with emphasis on discrepancies in reported findings across different experimental settings, potential crosstalk mechanisms, and the translational limitations of targeting these pathways for cardioprotection.</p><p><strong>Key scientific concepts: </strong>Current studies suggest that mitophagy in DIC follows a checkpoint-dependent pattern. Depending on DOX dose, exposure duration, and lysosomal degradative capacity, mitophagy may remove damaged mitochondria, but it may also worsen mitochondrial injury when initiation is insufficient, activation is excessive, or flux is stalled. In contrast, direct evidence for ER-phagy in DIC remains limited. This evidence is mainly derived from CCPG1-mediated protective ER-phagy in chronic fractionated DOX models and FAM134B-associated ER-phagy-related injury signals in acute high-dose injury models. Thus, the functional divergence of ER-phagy in DIC requires confirmation in additional experimental models with rigorous autophagic flux assessment. Mitochondria-associated ER membranes (MAMs) may coordinate mitophagy and ER-phagy by regulating calcium transfer, autophagosome formation, and receptor localization. Overall, current evidence does not support indiscriminate activation or inhibition of mitophagy and ER-phagy. Instead, future interventions may need to preserve flux-complete organelle clearance while avoiding excessive or stalled autophagic signaling. In addition, this framework may help generate research hypotheses that integrate cardioprotection with preservation of antitumor efficacy. However, most evidence comes from cell and animal studies, and further validation in human myocardial tissue and confirmation of cardiac target engagement are still needed.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying overlooked factors associated with multidrug-resistant tuberculosis: an ecological study across 201 countries and regions, 1990-2021.","authors":"Zihui Wang, Yuqi Chen, Jiamin Zhang, Mingshan Xue, Weilong Li, Zhiyin Zhang, Zhangkai J Cheng, Shaoqiang Li","doi":"10.1016/j.jare.2026.10.028","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.028","url":null,"abstract":"<p><strong>Background: </strong>Multidrug-resistant tuberculosis (MDR-TB) is a critical global health challenge. Whether environmental, nutritional, and socioeconomic factors are associated with MDR-TB remains insufficiently investigated.</p><p><strong>Methods: </strong>We analyzed outcome and exposure data from the Global Burden of Disease (GBD) Study and four additional databases covering 201 countries and territories from 1990 to 2021. Sex ratio, diabetes prevalence, and HIV/AIDS burden were regressed out of each outcome before analysis. Every candidate exposure was then both regressed against the confounder-adjusted outcome and correlated with it. Benjamini-Hochberg adjusted P values, together with correlation strength, determined which factors were retained for display. Effects are expressed as the absolute change per interquartile range (IQR) increase in exposure. Drug-susceptible tuberculosis served as a control outcome.</p><p><strong>Results: </strong>Per IQR of exposure, unsafe sanitation was associated with 13.9 more prevalent cases per 100,000 (95% CI 13.0-14.7) and 2.87 more deaths per 100,000 (2.72-3.03); unsafe water source with 11.2 (10.5-12.0) and 2.64 (2.49-2.78); and polluting fuels for cooking with 10.7 (9.8-11.6) and 2.74 (2.58-2.89). After further adjustment for GDP per capita and health expenditure, six associations remained significant, including unsafe sanitation, unsafe water source, absence of handwashing facilities and underweight (e.g., unsafe sanitation 2.8 per 100,000 per IQR, P < 0.001). Most of these associations were stronger for drug-susceptible disease than for MDR-TB, with the exception of diet low in fruits.</p><p><strong>Conclusions: </strong>Unsafe sanitation, unsafe water source, and polluting fuels for cooking are the population-level factors most strongly associated with MDR-TB burden. These associations are largely shared with drug-susceptible tuberculosis, supporting their integration into tuberculosis control efforts as a whole.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Maximizing crustaceans (shrimp, crab, and lobster) by-products value for optimum valorization practices: A comparative review of their active ingredients, extraction, bioprocesses and applications\" [J. Adv. Res. 57 (2024) 59-76].","authors":"Zuying Zhang, Zhenmin Ma, Lili Song, Mohamed A Farag","doi":"10.1016/j.jare.2026.09.018","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.018","url":null,"abstract":"","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network toxicology, machine learning, single-cell analysis, and molecular docking reveal 6PPD/6PPD-Q-associated atrial fibrillation signatures.","authors":"Wang Zhan, Jiulu Zhao, Yuan Li, Shuan Ran, Longyong Lai, Jie Wu, Sijie Zhou, Ran Li, Jikai Cui, Jiahong Xia","doi":"10.1016/j.jare.2026.10.032","DOIUrl":"10.1016/j.jare.2026.10.032","url":null,"abstract":"<p><strong>Introduction: </strong>Atrial fibrillation (AF) is the most prevalent sustained arrhythmia worldwide, and environmental factors are increasingly recognized as contributors to its complex pathogenesis. The tire antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidation product 6PPD-quinone (6PPD-Q) are emerging environmental contaminants with reported cardiotoxicity; however, their molecular relationship with AF remains unclear.</p><p><strong>Objectives: </strong>This study aimed to identify potential molecular targets and pathways that link 6PPD/6PPD-Q exposure to AF using an integrated network toxicology and machine learning strategy.</p><p><strong>Methods: </strong>Multicohort atrial microarray datasets from patients with AF were integrated to identify AF-related genes using differential expression analysis, weighted gene coexpression network analysis, and GeneCards database screening. Putative targets of 6PPD/6PPD-Q were predicted using multiple in silico databases and intersected with AF-related genes. Network toxicology, enrichment analysis, machine learning with SHAP interpretation, single-cell RNA sequencing, and molecular docking were utilized to identify and characterize hub genes. Key targets were validated using qRT-PCR and western blotting in human cardiac fibroblasts. A mouse exposure model was further used to assess AF inducibility, duration, and cardiac gene expression in vivo.</p><p><strong>Results: </strong>Sixteen putative AF-associated target genes of 6PPD/6PPD-Q were identified. Machine learning analysis highlighted four hub genes as key candidate hubs. Single-cell RNA analysis revealed cell type-specific expression, with enrichment in cardiomyocytes and vascular structural cells. Molecular docking predicted favorable binding interactions between 6PPD/6PPD-Q and the key target proteins. In vitro exposure to 6PPD or 6PPD-Q at the tested concentrations upregulated the mRNA and protein levels of all four candidate genes. In vivo exposure significantly increased pacing-induced AF inducibility, prolonged AF duration, and upregulated the expression of all these genes in cardiac tissues.</p><p><strong>Conclusion: </strong>These findings suggest that 6PPD and 6PPD-Q may contribute to AF by targeting specific genes and signaling pathways, with DDR1, BCHE, HTR2B, and KCNJ3 identified as core exposure-related hubs.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}