Journal of Advanced Research最新文献

{"title":"Corrigendum to “E3 ubiquitin ligase RNF128 attenuates colitis and colorectal tumorigenesis by triggering the degradation of IL-6 receptors” [J. Adv. Res. 72 (2025) 107–120]","authors":"Tian Sheng He, Kuntai Cai, Weiling Lai, Jingge Yu, Furong Qing, Ao Shen, Lina Sui, Wenji He, Weihua Wang, Qiuxiang Xiao, Xiong Lei, Tianfu Guo, Zhiping Liu","doi":"10.1016/j.jare.2025.10.013","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.013","url":null,"abstract":"The authors regret the oversight in Fig. 5J and Fig. S6A. While organizing the experimental data for this article, they unexpectedly found that some images in these figures were presented incorrectly.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"116 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314697","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":"Corrigendum to “Revolutionizing cancer treatment: QSAR-optimized sulfonamides as carbonic anhydrase inhibitors”. [J. Adv. Res. 74 (2025) S6]","authors":"Momen O. Khattab, Eman A. Mowafi, Mariam N. Hamed, Malak A. Mahmoud, Jana I. Hedar, Salma Elmallah","doi":"10.1016/j.jare.2025.09.027","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.027","url":null,"abstract":"The authors regret to inform the readers that the Principal Investigator, Dr. Salma Elmallah, was mistakenly listed only as a supervisor and not included in the author list.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"102 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314699","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":"Targeting PLOD2 induces epithelioid differentiation and improves therapeutic response in sarcomatoid renal cell carcinoma","authors":"Xiangyu Chen, Dongkui Xu, Yu Ji, Xichen Dong, Xiaomei Dong, Zihan Li, Jingyu Tan, Qianqian Sun, Huixian Xin, Ziwei Liu, Qing Deng, Tao Wen, Yanjun Jia, Xuhui Zhu, Jian Liu","doi":"10.1016/j.jare.2025.10.022","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.022","url":null,"abstract":"<h3>Introduction</h3>Sarcomatoid renal cell carcinoma (sRCC), a lethal variant arising through sarcomatoid dedifferentiation of epithelioid RCC (eRCC), poses significant clinical challenges due to the lack of molecular biomarkers and limited therapeutic options, with a median survival time for patients of less than 12 months.<h3>Objectives</h3>To dissect the molecular basis of sarcomatoid dedifferentiation and develop novel therapeutic strategies for sRCC.<h3>Methods</h3>Guided by the coprogenitor theory and tumor plasticity principles, we developed a differentiation-induction strategy targeting sarcomatoid dedifferentiation. Integrated transcriptomic and proteomic profiling revealed PLOD2 as a candidate therapeutic target. Spatial profiling of clinical sRCC specimens revealed selective PLOD2 overexpression in sarcomatoid components. Functional assays, including genetic ablation and pharmacological inhibition, were performed in sRCC cell lines and xenograft models to validate the role of PLOD2 in conferring sarcomatoid dedifferentiation plasticity and sarcomatoid morphology. Therapeutic significance was evaluated by PLOD2 intervention alone or in combination with conventional therapies (doxorubicin, gemcitabine, IFN-α, and axitinib).<h3>Results</h3>Compared with neighboring epithelioid RCC and adjacent normal components, PLOD2 expression was markedly upregulated in sarcomatoid regions. PLOD2 fuelled sarcomatoid dedifferentiation plasticity by activating cancer stemness, dedifferentiation, and EMT, partially via downstream activation of DCLK1, a cancer stem cell marker. PLOD2 ablation reversed sarcomatoid phenotypes, restored epithelioid differentiation, and sensitized tumors to conventional RCC therapies. Notably, minoxidil, an FDA-approved PLOD2 inhibitor, effectively suppressed sarcomatoid features and synergized with standard treatments in preclinical models.<h3>Conclusion</h3>Targeting PLOD2-mediated tumor plasticity represents a novel differentiation-inducing strategy to reprogram sRCC into therapy-responsive epithelioid states. The repurposing potential of minoxidil provides an immediate translatable strategy to improve clinical outcomes in this treatment-resistant malignancy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"4 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306311","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":"Anthocyanin-mediated epigenetic modifications: a new perspective in health promoting and disease prevention","authors":"Dongbao Cai, Yuxi Li, Dawei Sun, Yulin Zhang, Weibin Bai, Xusheng Li","doi":"10.1016/j.jare.2025.10.021","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.021","url":null,"abstract":"<h3>Background</h3>Epigenetic modifications play a pivotal role in the onset and progression of various diseases and are closely related to diet and environmental factors. Anthocyanins, a common dietary polyphenol, possess the potential to promote human health, serve as promising epigenetic modulators.<h3>Aim of review</h3>This review summarizes recent advancements in the role of anthocyanins in health promoting and disease prevention through the modulation of epigenetic modifications, focusing on clinical trials as well as in vivo and in vitro studies. It comprehensively explores the primary functions, specific mechanisms, challenges, and future perspectives of anthocyanins as epigenetic modulators, particularly in the context of DNA methylation, non-coding RNAs (ncRNAs), and histone modifications.<h3>Key scientific concepts of review</h3>Anthocyanins-mediated epigenetic modifications primarily influence genome stability, regulate gene expression, and modify chromatin structure, thus contributing to disease prevention and intervention. Anthocyanins are shown to impact DNA methylation patterns, maintaining homeostasis and alleviating abnormal DNA methylation in disease states. Regarding ncRNAs, anthocyanins alter the expression of miRNAs and lncRNAs, thereby modulating transcriptional repression or activation to mitigate the severity of diseases. Beyond DNA methylation and ncRNAs, anthocyanins also regulate histone modifications, promoting health and preventing disease by alleviating the abnormalities of histone-modifying enzymes. The development of targeted delivery systems for anthocyanins, the exploration of the anthocyanins-gut microbiota-epigenetics relationship, the investigation of anthocyanins’ effects on intergenerational inheritance, and attention to dietary patterns rich in anthocyanins are crucial areas for future research. Moreover, more extensive and effective clinical trials are needed to facilitate the broader application of anthocyanins in epigenetic-related diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"26 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306313","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":"Risperidone induces osteoporosis and neuropsychiatric treatment resistance via SMPD1-lysosome-mediated ferroptosis: dual rescue by active vitamin D analog ED-71","authors":"Yajun Cui, Ke Ma, Lingshuang Li, Xuejie Lin, Yu Ji, Haipeng Si, Hongrui Liu, Minqi Li","doi":"10.1016/j.jare.2025.10.017","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.017","url":null,"abstract":"<h3>Introduction</h3>Risperidone (RIS), a second-generation antipsychotic for schizophrenia (SZ), is linked to osteoporosis and suboptimal symptom resolution. The shared cellular mechanisms underlying these cross-tissue toxicities (bone and hippocampus) remain undefined, hindering therapeutic advancement.<h3>Objectives</h3>To determine if RIS induces toxicity in osteoblasts and hippocampal GABAergic neurons via the acid sphingomyelinase (SMPD1)-lysosome axis, and to evaluate the therapeutic potential of eldecalcitol (ED-71), an active vitamin D analog, in mitigating these effects.<h3>Methods</h3>Dizocilpine-induced SZ mice were used to evaluate bone loss and psychiatric symptoms. Primary osteoblasts induced from bone marrow mesenchymal stem cells (BMSCs) and MC3T3-E1 osteoblasts, as well as primary hippocampal neurons and HT22 hippocampal neurons, were treated with RIS to evaluate ferroptosis, lysosomal dysfunction, and SMPD1 activity. Key techniques included micro-CT, histomorphometric staining, behavioral tests, enzyme-linked immunosorbent assay, RNA sequencing, targeted lipidomics analysis, molecular dynamics simulations, and isothermal titration calorimetry assays. Virtual drug screening was used to identify potential RIS-SMPD1 interaction antagonists, with the identified candidate ED-71 further validated thereafter.<h3>Results</h3>RIS targeted lysosomes, causing dysfunction and membrane permeabilization, which drove ferroptosis in osteoblasts and hippocampal GABAergic neurons. Mechanistically, RIS bound to SMPD1 at ARG294, inhibiting its activity and triggering lysosomal phospholipid accumulation and ferroptosis. ED-71 disrupted RIS-SMPD1 interactions, restored lysosomal integrity, mitigated hyperprolactinemia/sympathetic overactivation, and synergized with RIS to enhance antipsychotic efficacy and prevent osteoporosis in SZ models.<h3>Conclusion</h3>This study identifies SMPD1 activation as a therapeutic target to counteract RIS-induced ferroptosis in bone and hippocampus. The dual-action mechanism of ED-71 provides a novel strategy for SZ intervention, simultaneously addressing psychiatric symptoms and osteoporotic complications.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"21 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295233","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":"Exosomes derived from M1-macrophage promote enteric neuronal injury via MMP8-TGF-β pathway","authors":"Yuqiong Chen, Kai Song, Yi Zheng, Chaoting Lan, Yide Mu, Zuyi Ma, Gen Chen, Yun Zhu, Yongwei Huang, Jiazhang Chen, Shenwei Huang, Qiuming He, Lihua Huang, Xiaoyu Zuo, Fenjie Li, Jixiao Zeng, Huimin Xia, Yan Zhang","doi":"10.1016/j.jare.2025.10.020","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.020","url":null,"abstract":"<h3>Introduction</h3>Enteric neuronal injury significantly contributes to gastrointestinal motility disorders. While macrophages are known to interact closely with enteric neurons and modulate intestinal homeostasis, their specific impact on enteric neuronal survival and injury remains poorly understood.<h3>Objective</h3>This study aimed to explore the potential contribution of macrophage-derived exosomes to enteric neuronal injury and investigate the underlying mechanisms.<h3>Methods</h3>We established a benzalkonium chloride (BAC)-induced enteric neuronal injury mouse model and assessed the effects of macrophage depletion on gastrointestinal motility and neuronal density. In vitro, enteric neurons were co-cultured with macrophages to examine the role of macrophage-derived exosomes in neuronal apoptosis. M1 macrophage-derived exosomes were isolated and characterized to elucidate potential mechanisms both <em>in vitro</em> and in vivo.<h3>Results</h3>Macrophage depletion partially rescued gastrointestinal dysmotility and enteric neuronal injury in BAC-treated mice. In vitro studies confirmed that M1 macrophage-derived exosomes promoted neuronal apoptosis. We identified matrix metalloproteinase 8 (MMP8) as enriched in M1 macrophage-derived exosomes, promoting the activation of the TGF-β signaling pathway and inducing neuronal apoptosis. Exosomes derived from M1 macrophages exacerbated neuronal injury in BAC mice, while inhibiting MMP8 partially mitigated neuronal injury and restored intestinal function. Additionally, elevated serum exosomal MMP8 levels were identified as a potential marker for Hirschsprung’s disease, a typical gastrointestinal motility disorder.<h3>Conclusion</h3>M1 macrophages induce enteric neuronal injury via exosomal MMP8-mediated TGF-β signaling, highlighting a potential therapeutic target for gastrointestinal motility disorders.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"58 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288905","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":"KDM6A/MMP-3 epigenetic axis governs macrophage senescence after spinal cord injury for mediating the regenerative niche to promote neurological repair","authors":"Jinyun Zhao, Xiaolong Sheng, Yinghe Ding, Haicheng Wen, Lifu Zheng, Yi Sun, Rundong He, Chengjun Li, Tian Qin, Tianding Wu, Liyuan Jiang, Hongbin Lu, Yong Cao, Jianzhong Hu, Chunyue Duan","doi":"10.1016/j.jare.2025.10.019","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.019","url":null,"abstract":"<h3>Introduction</h3>Spinal cord injury (SCI) stands as the primary cause of disability, still lacking a clear pathogenesis and effective treatment. The role of macrophages is particularly unclear in SCI, especially regarding cellular senescence. Additionally, the mechanisms driving macrophage senescence after SCI, the release of senescence-associated secretory phenotype (SASP) factors that affect the regenerative niche, and their contributions to SCI progression remain elusive.<h3>Objectives</h3>To investigate the role and underlying mechanism of Ubiquitously transcribed tetratricopeptide repeat X chromosome (UTX) in regulating macrophage senescence following SCI.<h3>Methods</h3>A contusive SCI model was constructed to explore the presence of senescent macrophages. After screening for UTX by a PCR array, conditioned knockout UTX mice (LysM-Cre; UTX^flox/flox) was constructed to explore the effect of UTX on macrophage senescence to influence angiogenesis and neurological function. Furthermore, RNA-seq and ChIP-seq were carried out to screen the downstream target gene Matrix Metalloprotease-3 (MMP-3). At last, RNA-seq was performed to explore the effect of MMP-3 on endothelial cells in vitro.<h3>Results</h3>An elevated presence of lysine demethylase 6A (Kdm6a/UTX), a special epigenetic regulatory modifier, was observed in macrophage senescence after SCI. Conditional deletion of UTX not only prevented macrophage senescence, but also enhanced the formation of a regenerative niche that protected endothelial cells from senescence and improved their proliferation. Mechanistically, UTX epigenetically regulated MMP-3 transcription through demethylating histone H3 lysine di/trimethylation (H3K27me2/3) at its promoter region. This led to senescent macrophages releasing MMP-3, a key SASP factor that disrupts the local microenvironment and impairs spinal cord repair post-injury. Notably, MMP-3 could act as a pro-senescent agent by senescent macrophages to propagate cellular senescence in endothelial cells (ECs), exacerbating cellular senescence in the injured region.<h3>Conclusions</h3>Our findings elucidate the KDM6A/MMP-3 epigenetic regulatory axis, which governs macrophage senescence and shapes a pro-regenerative microenvironment after SCI. Targeting this pathway promotes angiogenesis and facilitates neural repair, highlighting its potential as a therapeutic target for improving functional recovery after SCI.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"28 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295229","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":"Machine learning for food flavor prediction and regulation: models, data integration, and future perspectives","authors":"Xinyu Ge, Yongjie Zhou, Qing Li, Yuqing Tan, Yongkang Luo, Hui Hong","doi":"10.1016/j.jare.2025.10.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.018","url":null,"abstract":"<h3>Background</h3>Flavor is a central attribute of food quality, shaping consumer preferences and market performance. Traditional evaluation methods, such as sensory panels and basic assays, are often constrained by subjectivity, low throughput, and limited scalability. With the rise of high-throughput technologies and multimodal datasets, machine learning (ML) has emerged as a promising tool for deciphering and regulating complex flavor systems.<h3>Aim of review</h3>This review examines current flavor detection techniques and the application of ML across diverse domains. It compares supervised learning models (SVM, DT), ensemble algorithms (XGBoost, LightGBM), and deep learning approaches (CNN, ANN). This review also discusses the contribution of three major data dimensions to flavor prediction, as well as future prospects in the field. ML enables precise flavor prediction, compound screening, and real-time process control. To support these tasks, researchers have developed integrated analytical systems that combine electronic nose (E-nose), electronic tongue (E-tongue), gas chromatography–mass spectrometry (GC–MS), and gas chromatography–ion mobility spectrometry (GC-IMS). Ensemble learning and deep learning models show strong performance when handling complex, nonlinear datasets. Explainable artificial intelligence (XAI) tools such as Shapley Additive Explanations (SHAP) improve model transparency by linking predictions to underlying features. ML models further enhance both prediction accuracy and generalizability. Innovations such as attention mechanisms, graph neural networks, and digital twins support dynamic flavor modulation. ML also aids in identifying key flavor compounds and genotype-phenotype relationships, accelerating breeding and formulation.<h3>Key scientific concepts of review</h3>ML is opening up new technological avenues in flavor science, with significant potential to predict and control flavor formation mechanisms, verify product authenticity, and support the targeted design of flavor-active compounds that align with consumer expectations for sensory appeal.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"24 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295232","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":"Bridging traditional and deep learning methods in H&E histological image normalization: a comprehensive review and introducing a novel framework for comparative analyses","authors":"Behnaz Haji Molla Hoseyni, Sevda Imany, Ahmadreza Iranpour, Maryam Mehrabani, Sina Seifouri, Maryam Rafieipour-Jobaneh, Sina Firuzbakht, Ali Masoudi-Nejad","doi":"10.1016/j.jare.2025.09.049","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.049","url":null,"abstract":"<h3>Background</h3>Histology images are a cornerstone of pathology, which allow automated analysis for disease diagnosis. However, variations in staining and image acquisition processes significantly affect the performance of these algorithms. Histology image normalization is method to achieve uniformity in image color distributions, which will enhance the accuracy and consistency of automated analysis.<h3>Aim of review</h3>This review was conducted with the aim of assessing normalization methods and comparing them in an empirical manner to help researchers choose the most appropriate method for their study. It also aims to assist academics and professionals involved in automated image analysis and digital pathology.<h3>Key scientific concepts of review</h3>This review categorizes normalization techniques into four groups: deep learning-based approaches (e.g., GANs, autoencoders, diffusion models), traditional methods (e.g., deconvolution, histogram matching), hybrid models, and a novel signal processing-based method. It also introduces a new deep learning framework for evaluating normalization strategies and experimentally compares eight state-of-the-art methods on histopathology images. The results highlight the strengths and limitations of each approach, helping researchers and professionals choose suitable methods for their needs. In addition, the review emphasizes the impact of color variation on the accuracy of computer-aided diagnosis (CAD) systems and the importance of preserving biological information during normalization. Finally, it outlines directions for future research, including integrating normalization with data augmentation and exploring information preservation beyond cancer subtype.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"78 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283137","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":"Preserved ratio impaired spirometry, plasma proteomics, and incident heart failure","authors":"Yang Geng, Yi Ding, Yalong Pei, Xiya Zhou, Xujia Lu, Mingcan Xu, Yan Borné, Chaofu Ke","doi":"10.1016/j.jare.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.jare.2025.10.009","url":null,"abstract":"<h3>Introduction</h3>Epidemiological evidence suggests the association of preserved ratio impaired spirometry (PRISm) at baseline with the risk of heart failure (HF), however, the associations between transitions of PRISm and incident HF remain to be clarified. Furthermore, the causal relationship and underlying biological mechanisms linking PRISm and HF are unclear.<h3>Objectives</h3>This study aimed to investigate the association between the normal-PRISm transition and incident HF, and further evaluate the causal relationship and underlying molecular mechanisms linking PRISm and HF.<h3>Methods</h3>A total of 32,202 individuals with repeated spirometry and 40,047 individuals with proteomic data were included from the UK Biobank. Cox proportional hazards models were employed to estimate the association between the normal-PRISm transition and HF risk. Mendelian randomization (MR) analysis was performed to investigate the causal relationship between PRISm and HF. Mediation analysis was conducted to elucidate the mediation effects of 2,923 plasma proteins.<h3>Results</h3>Compared with consistent normal spirometry, the normal-PRISm transition was associated with an elevated risk of HF (hazard ratio: 1.814, 95% CI: 1.128, 2.919). The MR suggested a causal link between PRISm and HF (odds ratio: 1.488, 95% CI: 1.040, 2.130). In addition, 672 proteins demonstrated significant mediation effects, and the overall proteomic score mediated approximately 59.63% (95% CI: 46.98%, 77.12%) of the relationship between PRISm and HF.<h3>Conclusion</h3>Individuals with the normal-PRISm transition were at an elevated risk of HF. The MR results suggested the causal link between PRISm and HF, and a variety of plasma proteins substantially mediated the relationship between PRISm and HF.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"135 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283077","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}