iMeta最新文献

{"title":"Early gut microbial and metabolic dysregulation with subclinical cardiac alterations in a nonhuman primate model of Rett syndrome","authors":"Ting Zhang,&nbsp;Xiaopeng Wang,&nbsp;Peng Li,&nbsp;Junyu Zhang,&nbsp;Wenjie Sun,&nbsp;Zhen Zhang,&nbsp;Yan Zhuo,&nbsp;Wenting Guo,&nbsp;Yongchang Chen","doi":"10.1002/imt2.70137","DOIUrl":"https://doi.org/10.1002/imt2.70137","url":null,"abstract":"<p>Longitudinal multi-omics profiling of a nonhuman primate Rett syndrome (RTT) model reveals early systemic alterations. RTT monkeys exhibited postnatal growth retardation, intestinal structural abnormalities, and low-grade systemic inflammation. Gut microbiome analysis showed delayed microbial maturation and age-discordant dysbiosis, including altered <i>Firmicutes/Bacteroidetes</i> ratios and persistent community restructuring. Fecal metabolomics revealed reduced short-chain fatty acids (SCFAs), disrupted microbe–metabolite networks, and broad alterations in lipid, amino acid, and energy metabolism. Electrocardiogram (ECG) identified prolonged corrected QT interval (QTc) and subclinical cardiac electrophysiological changes. Integrated multi-omics analyses indicate that RTT involves early, coordinated dysregulation across gut microbial, metabolic, immune, and peripheral physiological systems, supporting its characterization as a systemic disorder from the early postnatal stage.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148532958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating the future of nano-pesticides: A perspective on design, efficacy, mechanisms, and environmental stewardship","authors":"Xile Deng,&nbsp;Feiying Zhu,&nbsp;Heng Qiao,&nbsp;Wenjie Shangguan,&nbsp;Qin Yu,&nbsp;Sandeep Sharma,&nbsp;Vijayakumar Shanmugam,&nbsp;Yanan Deng,&nbsp;Yudan Wu,&nbsp;Pengyue Zhao,&nbsp;Ullah Farman,&nbsp;Lidong Cao,&nbsp;Shuo Yan,&nbsp;Zhichao Dong,&nbsp;Lianyang Bai","doi":"10.1002/imt2.70129","DOIUrl":"https://doi.org/10.1002/imt2.70129","url":null,"abstract":"<p>Nano-pesticides are driving a paradigm shift toward sustainable plant protection. This review systematically synthesizes recent advances across four interconnected domains: (i) intelligent formulation design for targeted delivery and controlled release; (ii) interfacial behavior regulation to enhance foliar deposition; (iii) multi-omics elucidation of synergistic efficacy and molecular interactions; and (iv) environmental fate management, including risk mitigation and microbiome remediation. By integrating these multiscale innovations, the field is advancing nano-enabled crop protection from laboratory research toward field application. Collectively, this convergence provides a scientific foundation and interdisciplinary roadmap needed to build next-generation agricultural systems that are resource-efficient and ecologically compatible.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148522929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanopore direct RNA sequencing and the epitranscriptome: Advances in mapping native RNA landscapes","authors":"Tianyuan Zhang,&nbsp;Jia Li,&nbsp;Chao Tang,&nbsp;You Wu,&nbsp;Hao Wu,&nbsp;Xi-Tong Zhu,&nbsp;Ziyang Luo,&nbsp;Hang Qin,&nbsp;Lishan Ding,&nbsp;Yu Zeng,&nbsp;Shiou Yih Lee,&nbsp;Xiaotao Shen,&nbsp;Shiwen Gao,&nbsp;Zhaoyang Tian,&nbsp;Qian Tang,&nbsp;Mian Li,&nbsp;Muhammad Tahir Ul Qamar,&nbsp;Yang Dong,&nbsp;Komivi Dossa,&nbsp;Yaxuan Zhang,&nbsp;Hu Chen,&nbsp;Sanqi An,&nbsp;Xiang Yu,&nbsp;Lu Chen,&nbsp;Dingjie Wang,&nbsp;Shengli Li,&nbsp;Ling-Ling Chen,&nbsp;Yanqiang Li","doi":"10.1002/imt2.70136","DOIUrl":"https://doi.org/10.1002/imt2.70136","url":null,"abstract":"<p>Nanopore direct RNA sequencing (DRS) has transformed transcriptomics by enabling single-molecule, long-read sequencing of native RNA without the need for reverse transcription or amplification. In contrast to short-read RNA-seq and cDNA-based long-read approaches, DRS can simultaneously capture multiple RNA modifications, full-length transcript architecture, alternative splicing patterns, and poly(A) tail features within individual molecules, thereby providing an integrated view of transcriptomic and epitranscriptomic regulation. In this comprehensive review, we outline the biophysical principles underlying nanopore DRS and trace its technological evolution. We compare its performance with short-read RNA sequencing, long-read cDNA sequencing, and conventional RNA-modification mapping strategies, highlighting its advantages in isoform-resolved quantification and multilayer RNA feature integration, while also clarifying contexts in which alternative or combined approaches may be more appropriate for robust biological interpretation. We further summarize optimized experimental workflows, including library construction strategies tailored to diverse RNA biotypes (mRNA, rRNA, tRNA, circRNA, miRNA, and nonpoly(A) transcripts), as well as recommended quality-control procedures and sequencing optimization practices. Emphasizing recent computational advances and translational applications of DRS, we cover state-of-the-art algorithms for RNA modification detection, transcript reconstruction, and isoform quantification. We also propose analytical pipelines for poly(A) tail length inference and integrative frameworks that jointly analyze these regulatory layers. We distinguish direct nanopore signals from computational inferences to define confidence levels and emphasize benchmarking and orthogonal validation of readouts. Practical implementation examples are included to facilitate reproducible analysis. Finally, we highlight emerging applications of integrated DRS, including the resolution of complex transcriptomes, the characterization of coordinated epitranscriptomic regulation, and the identification of disease-associated RNA signatures. We also discuss current technical challenges and future perspectives, particularly in relation to multi-omics integration and the broader deployment of DRS in precision medicine as well as in plant and animal research.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148532693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"microeco 2: A comprehensive R package for downstream analysis of microbiome omics data","authors":"Chi Liu,&nbsp;Xiangzhen Li,&nbsp;Felipe R. P. Mansoldo,&nbsp;Tong Chen,&nbsp;Fanzheng Meng,&nbsp;Ruixiang Tang,&nbsp;Siyu Zhou,&nbsp;Qinghua Yang,&nbsp;Ruixin Shao,&nbsp;Minjie Yao","doi":"10.1002/imt2.70132","DOIUrl":"https://doi.org/10.1002/imt2.70132","url":null,"abstract":"<p>Efficient downstream analysis of microbiome data remains a major challenge for researchers. Since its initial release in late 2020, the R microeco package has been widely used for downstream statistical analysis and visualization of omics data, such as amplicon sequencing. Compared with its initial release, the current second version of the microeco package has undergone extensive updates and enhancements. The key upgrades include: (1) The addition of classes for data normalization and machine learning, respectively; (2) The incorporation of additional analytical methods and the addition of functions across various classes; (3) Optimization of the parameter system to expand the applicable scenarios of relevant methods; (4) Code restructuring to enhance the connectivity between statistical analysis and visualization within each class; (5) Extension of certain functions to enable the analysis of abundance data in complex formats generated from bioinformatic analyses of metagenomic/metatranscriptomic data; (6) Incorporation of several analytical methods commonly used in transcriptomic and metabolomic data analyses. Overall, the microeco package 2.0 offers broader method coverage and a wider range of application scenarios compared to the previous version and other existing R packages. The steady growth in user downloads demonstrates that the microeco package, which is built on R6 (a class-based object-oriented programming system for R), has established a broad and active user base. The second version of the microeco R package is open-source and available on the Comprehensive R Archive Network and GitHub (https://github.com/ChiLiubio/microeco).</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148533822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial keystone taxa and metabolic signatures in centenarians regulate intestinal homeostasis during aging","authors":"Wei-Chuan Lin,&nbsp;Cui Zhang,&nbsp;He-Hua Lei,&nbsp;Zheng Cao,&nbsp;Xin Gao,&nbsp;Wen-Kai Yu,&nbsp;Xin-Zhi Li,&nbsp;Qing-Wei Xiang,&nbsp;Zhi-Wen Zhang,&nbsp;Shi-Fu Pang,&nbsp;Wei-Fei Luo,&nbsp;Deng-Hui Xie,&nbsp;Li-Min Zhang,&nbsp;Gang Chen","doi":"10.1002/imt2.70134","DOIUrl":"https://doi.org/10.1002/imt2.70134","url":null,"abstract":"<p>Microbial networks and keystone taxa play pivotal roles in maintaining gut microecological stability and host homeostasis, irrespective of their abundance. However, most previous studies of aging-associated gut microbiota have relied on abundance-based analyses, largely overlooking microbial networks and microbe-host interactions. Here, we employed a co-occurrence network approach to identify keystone taxa during aging in humans and mice. We found that centenarians harbor distinctive keystone taxa dominated by members of <i>Clostridium</i>, of which <i>Clostridium scindens</i> (<i>C. scindens</i>) can significantly enhance microbial network stability, probably contributing to longevity and reduced susceptibility to age-related diseases. Mechanistically, <i>C. scindens</i> produces indole-3-acetic acid (IAA) from tryptophan via the enzymes amidase (AMIE) and aldehyde dehydrogenase (ALDH). Oral administration of either <i>C. scindens</i> or IAA effectively mitigates intestinal aging by restoring gut barrier dysfunction in aged mice. Further analysis revealed that <i>C. scindens</i>-derived IAA restores intestinal dysfunction through activation of aryl hydrocarbon receptor (AHR) signaling, leading to upregulation of intestinal CLDN10, a key tight junction protein. Structurally, IAA enhances <i>Claudin</i>-<i>10</i> transcription by promoting AHR binding to its promoter region. Our findings provide new insights into the characterization of microbial networks in centenarians and highlight that <i>C. scindens</i> and IAA may contribute to healthy longevity by promoting gut microecological stability and host homeostasis.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative host–microbiome modeling uncovers the implication of oral–gut translocation in advanced cirrhosis","authors":"Yi Jin,&nbsp;Frederick Clasen,&nbsp;Fernando Garcia-Guevara,&nbsp;Sania Arif,&nbsp;Robert Schierwagen,&nbsp;Gholamreza Bidkhori,&nbsp;Michael Praktiknjo,&nbsp;Maximilian J. Brol,&nbsp;Frank E. Uschner,&nbsp;Florence A. Castelli,&nbsp;Nicolas Pons,&nbsp;Benoit Quinquis,&nbsp;Nathalie Galleron,&nbsp;Kevin Da Silva,&nbsp;Christophe Junot,&nbsp;Debbie L. Shawcross,&nbsp;David L. Moyes,&nbsp;Rajiv Jalan,&nbsp;S. Dusko Ehrlich,&nbsp;Vishal C. Patel,&nbsp;Jonel Trebicka,&nbsp;Saeed Shoaie","doi":"10.1002/imt2.70131","DOIUrl":"https://doi.org/10.1002/imt2.70131","url":null,"abstract":"<p>Liver cirrhosis is associated with profound disruption of host–microbiome metabolic interactions. Using paired oral and fecal metagenomics combined with genome-scale metabolic modeling, we investigated how microbial translocation along the oral–gut axis influences microbial metabolism at different cirrhosis severities. Reactobiome-based functional profiling revealed progressive metabolic convergence between oral and gut microbiomes, quantified by a decrease in oral–gut metabolic distance. Translocation-associated microbial species enriched in patients with cirrhosis were predicted to have elevated capacities for ammonia and acetate production. Microbial-community and host metabolic modeling further suggested that these microbial metabolic shifts may influence host energy metabolism and redox balance across the liver, brain, and skeletal muscle. Together, these findings suggest a potential acetate-ammonia metabolic axis linking oral–gut microbial translocation with systemic metabolic stress in advanced cirrhosis.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70131","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148532689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic microbial communities for engineering climate-smart biofertilizers","authors":"Yan Liu,&nbsp;Yue Chen,&nbsp;Yanxue Yu,&nbsp;Che Ok Jeon,&nbsp;Mohammad Bahram,&nbsp;Junfeng Zhai,&nbsp;Hailei Wei,&nbsp;Fuqiang Wang,&nbsp;Xiaofeng Cao,&nbsp;Baolei Jia","doi":"10.1002/imt2.70140","DOIUrl":"https://doi.org/10.1002/imt2.70140","url":null,"abstract":"<p>Global agricultural productivity is increasingly destabilized by climate change—driven droughts, floods, extreme heat, and severe storms. Although the climate-smart agriculture (CSA) framework addresses these challenges, implementation has focused mainly on plant genetics and agronomic inputs, leaving the adaptive potential of the crop microbiome underexplored. Here, we examine the agricultural use of synthetic microbial communities (SynComs) through the “crop holobiont” concept, in which plants and their associated microbiota function as an integrated, responsive system rather than through plant genomes alone. Pioneer plants in extreme environments may serve as reservoirs of stress-adapted microbes and provide a strategic toolkit for advancing CSA. SynComs assembled from these microbes can act not only as nutrient suppliers but also as dynamic physiological modulators that enhance crop phenotypic plasticity under climatic stress. We propose a roadmap for crop microbiology that integrates synthetic ecological engineering, with broad implications for CSA.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148532950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From prediction to actionable mechanisms: Explainable multi‑omics AI for farm‑to‑fork postharvest preservation","authors":"Peihua Ma,&nbsp;Xiaoxue Jia,&nbsp;Bei Fan,&nbsp;Boqiang Li,&nbsp;Tao Lin,&nbsp;Jiping Sheng,&nbsp;Cheng-I Wei,&nbsp;Yingjian Lu,&nbsp;Yizhou Ma,&nbsp;Lin Chen,&nbsp;Songtao Jiu,&nbsp;Fengzhong Wang","doi":"10.1002/imt2.70139","DOIUrl":"https://doi.org/10.1002/imt2.70139","url":null,"abstract":"<p>Graphical overview of explainable artificial intelligence (XAI) for farm-to-fork postharvest preservation. Postharvest deterioration accumulates across orchard, packhouse, refrigerated transportation, warehouse, and distribution stages under fluctuating temperature, humidity, atmosphere, and mechanical stress. Multimodal data streams, including host omics, microbiome profiles, environmental sensing, RGB/hyperspectral/thermal imaging, spectroscopy, key genes, and logistics records, are integrated through a data lakehouse and analyzed by postharvest XAI models. Explainable modules, including SHapley Additive exPlanations (SHAP)/local attribution, graph neural network (GNN) explanation, pathway-constrained models, counterfactual reasoning, and stability/faithfulness auditing, convert black-box spoilage-risk prediction into interpretable biological mechanisms. These mechanisms guide actionable interventions such as antioxidant coating, elicitor spray, biocontrol consortia, packaging optimization, and gene-targeted strategies. Validation through storage trials, sensory evaluation, microbial testing, and sequencing closes the loop from prediction to explanation, intervention, and validated decision support.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148532959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-derived organoid-immune co-cultures integrated with multi-omics reveal immunotherapy resistance mechanisms in urothelial carcinoma","authors":"Shan Jiang,&nbsp;Yuxuan Song,&nbsp;Yun Peng,&nbsp;Ran Yan,&nbsp;Yunze Niu,&nbsp;Baoqiang Chen,&nbsp;Jiaxing Lin,&nbsp;Jilin Wu,&nbsp;Shixiang Wang,&nbsp;Yiqing Du,&nbsp;Caipeng Qin,&nbsp;Yihan Lin,&nbsp;Tao Xu","doi":"10.1002/imt2.70130","DOIUrl":"https://doi.org/10.1002/imt2.70130","url":null,"abstract":"<p>Immunotherapy resistance presents a formidable challenge in tumor biology. While fibroblast growth factor receptor 3 (FGFR3) serves as a pivotal oncogenic driver in a multitude of cancers, the exploration of its role in immune checkpoint inhibitor (ICI) resistance remains scarce, thus impeding a deeper understanding of the tumor immune microenvironment (TIME) in the era of immunotherapy. Employing patient-derived urothelial carcinoma (UC) organoids and co-cultured systems, along with single-cell RNA sequencing (scRNA-seq), whole-exome sequencing (WES), bulk RNA-seq, and CUT&amp; Tag epigenomics in UC cohorts, we identified and characterized the key downstream mediators of FGFR3. The TIME associated with <i>FGFR3</i> mutations exhibited a depletion of NK and CD8⁺ T cells, while simultaneously harboring an accumulation of exhausted effectors, correlating with diminished ICI response. Erdafitinib reprogrammed this “cold” TME into an inflamed state through a novel FGFR3–STAT5–IRF2 signaling cascade. These findings, corroborated by a wealth of evidence, advocate for the combination of FGFR3-targeted therapy with immunotherapy for UC, bridging critical pre-clinical and clinical insights.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70130","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148532690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metal-dependent regulated cell death: Molecular architecture and translational frontiers","authors":"Haoliang Hu,&nbsp;Zhe Chen,&nbsp;Yaqi Li,&nbsp;Jiayi Peng,&nbsp;Jiangang Cao,&nbsp;Hong Zhou,&nbsp;Mengqi Wang,&nbsp;Yuejia Du,&nbsp;Hailin Wu,&nbsp;Huiqin Zhao,&nbsp;Shifang Huang,&nbsp;Dianmei Yu,&nbsp;Meiqing Liu,&nbsp;Olga V. Shevchenko,&nbsp;Natalia Yu. Matveeva,&nbsp;Yiyuan Yang,&nbsp;Kerui Huang,&nbsp;Deguan Lv,&nbsp;Junxia Min,&nbsp;Linxi Chen,&nbsp;Fudi Wang","doi":"10.1002/imt2.70141","DOIUrl":"https://doi.org/10.1002/imt2.70141","url":null,"abstract":"<p>Intracellular metal dyshomeostasis has emerged as a key regulator of specialized regulated cell death (RCD) programs, challenging classical views that regard necrosis as entirely accidental. This review systematically delineates the molecular architecture and translational trajectories underlying metal-dependent RCD, including iron-driven ferroptosis, copper-mediated cuproptosis, and additional emerging modalities such as calcicoptosis, necrosis by sodium overload (NECSO), and the newly designated zincoptosis, mnoptosis, and coptosis. We examined distinct execution mechanisms, ranging from membrane lipid peroxidation and lipoylation-targeted proteotoxic stress to organelle-specific bioenergetic failure, which arise following disruption of compartmentalized metal-buffering networks. To bridge the persistent knowledge gap between foundational metallobiology and clinical application, we evaluated a bidirectional therapeutic framework: exploiting synthetic lethality and metabolic gating via clinical inducers (e.g., sorafenib, elesclomol) to selectively eliminate therapy-resistant malignancies while deploying targeted pathway inhibitors and systemic agonists (e.g., dipyridamole, omaveloxolone) to limit pathological tissue degeneration in ischemic and neurodegenerative disorders. Recognizing that off-target multiorgan toxicity and complex in vivo crosstalk among interconnected death pathways (e.g., disulfidptosis and PANoptosis) represent major translational challenges, we assessed advanced materials-science strategies designed to overcome these barriers. Specifically, we highlighted the integration of single-atom catalysts, stimuli-responsive nanomedicines, and biomimetic carriers engineered to spatiotemporally confine catalytic oxidative flux. Finally, we examined the systemic immunological consequences of targeted metal dysregulation, detailing how metal-induced immunogenic cell death and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway hyperactivation reshape immunosuppressive microenvironments and modulate sterile inflammation, thereby enhancing responsiveness to immune checkpoint blockade, providing a definitive molecular blueprint for next-generation precision therapeutics.</p>","PeriodicalId":73342,"journal":{"name":"iMeta","volume":"5 3","pages":""},"PeriodicalIF":44.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/imt2.70141","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148532600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}