MedComm最新文献

{"title":"Microbiome: A New Perspective on Immunotherapy for Metastatic Tumors","authors":"Hongquan Liu, Tianqi Wang, Jitao Wu","doi":"10.1002/mco2.70185","DOIUrl":"https://doi.org/10.1002/mco2.70185","url":null,"abstract":"<p>A recent study in <i>Cell</i> by researchers from the Netherlands Cancer Institute used multi-omics methods to explore the microbiome of metastatic tumors [<span>1</span>]. Analyzing over 4000 biopsy samples, they found correlations between microbial composition and tumor immunity and responses to immunotherapy. This comprehensive resource highlights the connection between tumor immunity and microbial dynamics, contributing to the development of immunotherapy strategies.</p><p>With the advancement of sequencing technology, there is a growing recognition of the vast array of symbiotic microorganisms that reside within various organisms. These symbiotic microbes exhibit intricate dynamic interactions with the host's immune system and are involved in various physiological processes. Recent research on symbiotic microbes has shifted our focus to the species and functions of tumor-associated microbes [<span>2</span>]. The intratumoral microbiome has been demonstrated to not only directly act on tumor cells, promoting or inhibiting their growth, but also indirectly regulate the immune escape mechanisms of tumors by influencing immune cells within the tumor microenvironment. Studies have revealed that gut microbiota can modulate the response to immune checkpoint blockade (ICB) therapy and traditional chemotherapy, as well as reshape the tumor microenvironment through microbes residing in primary tumors [<span>3</span>]. By offering a detailed fingerprint of an individual's immune status and responsiveness, the microbiome presents a transformative opportunity for personalized medicine. Based on unique microbial signatures, clinicians can customize immunotherapy to individual patients, enhancing outcomes, minimizing adverse effects, and improving quality of life and survival rates for metastatic tumor patients. However, numerous scientific questions remain to be addressed. For instance, the characteristics of the microbiome in metastatic tumors are still undetermined. Do the microbiomes of primary and metastatic tumors exhibit differences? Is the colonization of microbial species determined by tumor type or organ type? Additionally, the evolution of microbial populations during therapeutic interventions is also uncertain.</p><p>In Battaglia's work, researchers conducted a thorough analysis of 4160 metastatic tumor biopsy samples from 26 different tissues, using Kraken2, PathSeq, and an assembly-based approach along with corresponding genomics and transcriptomics data to precisely identify and quantify microbial communities within the metastatic tumors. This study revealed that bacterial DNA could be detected in metastatic tumors, and its diversity displayed a close correlation with tumor immune characteristics at the cellular and molecular levels. Among the findings, metastatic colorectal tumors exhibited the greatest species diversity, while head and neck metastatic tumors harbored a greater abundance of dominant bacteria.</p><p>Notably, what factors ","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896864","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":"Organoid-Guided Precision Medicine: From Bench to Bedside","authors":"Boqaing Tao,&nbsp;Xiaolan Li,&nbsp;Ming Hao,&nbsp;Tian Tian,&nbsp;Yuyang Li,&nbsp;Xiang Li,&nbsp;Chun Yang,&nbsp;Qirong Li,&nbsp;Qiang Feng,&nbsp;Hengzong Zhou,&nbsp;Yicheng Zhao,&nbsp;Dongxu Wang,&nbsp;Weiwei Liu","doi":"10.1002/mco2.70195","DOIUrl":"https://doi.org/10.1002/mco2.70195","url":null,"abstract":"<p>Organoid technology, as an emerging field within biotechnology, has demonstrated transformative potential in advancing precision medicine. This review systematically outlines the translational trajectory of organoids from bench to bedside, emphasizing their construction methodologies, key regulatory factors, and multifaceted applications in personalized healthcare. By recapitulating physiological architectures and disease phenotypes through three-dimensional culture systems, organoids leverage natural and synthetic scaffolds, stem cell sources, and spatiotemporal cytokine regulation to model tissue-specific microenvironments. Diverse organoid types—including skin, intestinal, lung, and tumor organoids—have facilitated breakthroughs in modeling tissue development, drug efficacy and toxicity screening, disease pathogenesis studies, and patient-tailored diagnostics. For instance, patient-derived tumor organoids preserve tumor heterogeneity and genomic profiles, serving as predictive platforms for individualized chemotherapy responses. In precision medicine, organoid-guided multiomics analyses identify actionable biomarkers and resistance mechanisms, while clustered regularly interspaced short palindromic repeats-based functional screens optimize therapeutic targeting. Despite preclinical successes, challenges persist in standardization, vascularization, and ethical considerations. Future integration of artificial intelligence, microfluidics, and spatial transcriptomics will enhance organoid scalability, reproducibility, and clinical relevance. By bridging molecular insights with patient-specific therapies, organoids are poised to revolutionize precision medicine, offering dynamic platforms for drug development, regenerative strategies, and individualized treatment paradigms.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897109","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":"Dual MNK/VEGFR2 Inhibitor JDB153 Enhances Immunotherapeutic Efficiency and Chemosensitivity in Lung Cancer","authors":"Maosen Xu,&nbsp;Li Xu,&nbsp;Tao Zhang,&nbsp;Xue Li,&nbsp;Ziqi Zhang,&nbsp;Ruolan Xia,&nbsp;Ning Jiang,&nbsp;Li Yang,&nbsp;Xiawei Wei","doi":"10.1002/mco2.70155","DOIUrl":"https://doi.org/10.1002/mco2.70155","url":null,"abstract":"<p>Lung cancer continues to be the primary cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant type. Dysregulation of protein translation that participates in cell proliferation is an important factor to define oncogenic processes and cancer development. The eukaryotic initiation factor 4E (eIF4E) regulates ribosomal translation of proteins from mRNA, and the mitogen-activated protein kinase interacting kinases (MNKs) is reported to be the only kinases that can phosphorylate eIF4E. Substantial previous work has proven that the MNK–eIF4E axis is usually dysregulated in many cancer types. Moreover, abnormal angiogenesis is essential for tumorigenesis and cancer progression, and vascular endothelial growth factors (VEGF) together with their receptors play multiple crucial roles in angiogenesis, especially VEGFR2. In this study, we report a novel dual MNK/VEGFR2 inhibitor named JDB153 and investigate its antitumor effects in NSCLC. JDB153 can effectively inhibit the phosphorylation of eIF4E and VEGFR2, suppress proliferation, migration and invasion, promote apoptosis, and induce cycle arrest of lung cancer cells. Importantly, JDB153 exhibits antitumor activity and synergizes with anti-PD-1 therapy and cisplatin with reliable safety. Our findings reveal the potential value of JDB153 in lung cancer as monotherapy or in combination with immunotherapy and chemotherapy, with the hope to provide a novel combinational strategy for NSCLC treatment clinically.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888853","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":"Molecular Hydrogen Therapy: Mechanisms, Delivery Methods, Preventive, and Therapeutic Application","authors":"Jiayi Jin,&nbsp;Lijun Yue,&nbsp;Maoru Du,&nbsp;Feng Geng,&nbsp;Xue Gao,&nbsp;Yuming Zhou,&nbsp;Qianqian Lu,&nbsp;Xiaohong Pan","doi":"10.1002/mco2.70194","DOIUrl":"https://doi.org/10.1002/mco2.70194","url":null,"abstract":"<p>Molecular hydrogen (H₂), recognized as the smallest gas molecule, is capable of permeating cellular membranes and diffusing throughout the body. Due to its high bioavailability, H₂ is considered a therapeutic gas for the treatment of various diseases. The therapeutic efficacy of hydrogen is contingent upon factors such as the administration method, duration of contact with diseased tissue, and concentration at targeted sites. H₂ can be administered exogenously and is also produced endogenously within the intestinal tract. A comprehensive understanding of its delivery mechanisms and modes of action is crucial for advancing hydrogen medicine. This review highlights H₂’s mechanisms of action, summarizes its administration methods, and explores advancements in treating intestinal diseases (e.g., inflammatory bowel disease, intestinal ischemia–reperfusion, colorectal cancer). Additionally, its applications in managing other diseases are discussed. Finally, the challenges associated with its clinical application and potential solutions are explored. We propose that current delivery challenges faced by H₂ can be effectively addressed through the use of nanoplatforms; furthermore, interactions between hydrogen and gut microbiota may provide insights into its mechanisms for treating intestinal diseases. Future research should explore the synergistic effects of H₂ in conjunction with conventional therapies and develop personalized treatment plans to achieve precision medicine.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880143","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":"The Third Pillar of Precision Medicine — Precision Delivery","authors":"Avnesh S. Thakor","doi":"10.1002/mco2.70200","DOIUrl":"https://doi.org/10.1002/mco2.70200","url":null,"abstract":"<p>Precision Medicine is thought of as having two main pillars: Precision Diagnosis and Precision Therapy. However, for Precision Medicine to reach its full potential, a third pillar is needed that we propose to call <i>Precision Delivery</i>. In the laboratory, many therapies show great efficacy when tested directly with target cells. However, upon clinical translation, they are often given via intravenous or oral administration, resulting in their systemic distribution. To ensure therapies reach target sites at the correct therapeutic levels, they are often given at higher concentrations. However, this can be associated with off-target effects, side-effects, and unwanted interactions. Delivery strategies can help mitigate this by “spatially re-coupling” therapies in vivo with target cells. This review explains the concept of <i>Precision Delivery</i>, which can be thought of as three interconnected, but independent, modules: targeted delivery, microenvironment modulation, and cellular interactions. While locoregional approaches directly deliver therapies into target tissues through endovascular, endoluminal, percutaneous, and implantation techniques, microenvironment modulation technologies facilitate the movement of therapies across biological barriers and through tissue matrices, so optimized therapies can reach and interact with target cells. We highlight new innovations driving advances in <i>Precision Delivery</i>, while also discussing the considerations and challenges that <i>Precision Delivery</i> faces as it becomes increasingly integrated into treatment workflows.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880144","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":"Self-Healing Hydrogels: Mechanisms and Biomedical Applications","authors":"Lingling Xue,&nbsp;Ran An,&nbsp;Junqi Zhao,&nbsp;Mengdi Qiu,&nbsp;Zhongxia Wang,&nbsp;Haozhen Ren,&nbsp;Decai Yu,&nbsp;Xinhua Zhu","doi":"10.1002/mco2.70181","DOIUrl":"https://doi.org/10.1002/mco2.70181","url":null,"abstract":"<p>Hydrogels have emerged as dependable candidates for tissue repair because of their exceptional biocompatibility and tunable mechanical properties. However, conventional hydrogels are vulnerable to damage owing to mechanical stress and environmental factors that compromise their structural integrity and reduce their lifespan. In contrast, self-healing hydrogels with their inherent ability to restore structure and function autonomously offer prolonged efficacy and enhanced appeal. These hydrogels can be engineered into innovative forms including stimulus-responsive, self-degradable, injectable, and drug-loaded variants, thereby enhancing their applicability in wound healing, drug delivery, and tissue engineering. This review summarizes the categories and mechanisms of self-healing hydrogels, along with their biomedical applications, including tissue repair, drug delivery, and biosensing. Tissue repair includes wound healing, bone-related repair, nerve repair, and cardiac repair. Additionally, we explored the challenges that self-healing hydrogels continue to face in tissue repair and presented a forward-looking perspective on their development. Consequently, it is anticipated that self-healing hydrogels will be progressively designed and developed for applications that extend beyond tissue repair to a broader range of biomedical applications.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70181","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865983","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":"Hypoxia-Driven Neurovascular Impairment Underlies Structural-Functional Dissociation in Diabetic Sudomotor Dysfunction","authors":"Xu Guo,&nbsp;Chao Zhang,&nbsp;Yuzhen Wang,&nbsp;Zhao Li,&nbsp;Yaxin Tan,&nbsp;Dongzhen Zhu,&nbsp;Wei Song,&nbsp;Yi Kong,&nbsp;Jinpeng Du,&nbsp;Yuyan Huang,&nbsp;Liting Liang,&nbsp;Jianjun Li,&nbsp;Mengde Zhang,&nbsp;Linhao Hou,&nbsp;Qinhua Liu,&nbsp;Feng Tian,&nbsp;Bingyang Yu,&nbsp;Yue Kong,&nbsp;Zhenyu Zhou,&nbsp;Xiaobing Fu,&nbsp;Sha Huang","doi":"10.1002/mco2.70173","DOIUrl":"https://doi.org/10.1002/mco2.70173","url":null,"abstract":"<p>Sudomotor dysfunction in diabetic patients increases the risk of fissures, infections, and diabetic foot ulcers (DFUs), thereby reducing the quality of life. Despite its clinical importance, the mechanisms underlying this dysfunction remain inadequately elucidated. This study addresses this gap by demonstrating that despite structural integrity, sweat glands (SGs) in diabetic individuals with DFUs, and a murine model of diabetic neuropathy (DN), exhibit functional impairments, as confirmed by histological and functional assays. Integrated transcriptome and proteome analysis revealed significant upregulation of the SG microenvironment in response to hypoxia, highlighting potential underlying pathways involved. In addition, histological staining and tissue clearing techniques provided evidence of impaired neurovascular networks adjacent to SGs. Single-cell RNA sequencing unveiled intricate intercellular communication networks among endothelial cells (ECs), neural cells (NCs), and sweat gland cells (SGCs), emphasizing intricate cellular interactions within the SG microenvironment. Furthermore, an in vitro SGC–NC interaction model (SNIM) was employed to validate the supportive role of NCs in regulating SGC functions, highlighting the neurovascular-SG axis in diabetic pathophysiology. These findings confirm the hypoxia-driven upregulation of the SG microenvironment and underscore the critical role of the neurovascular-SG axis in diabetic pathophysiology, providing insights into potential therapeutic targets for managing diabetic complications and improving patient outcomes.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865922","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":"Tissue Engineering and Regenerative Medicine: Perspectives and Challenges","authors":"Van T. Hoang,&nbsp;Quyen Thi Nguyen,&nbsp;Trang Thi Kieu Phan,&nbsp;Trang H. Pham,&nbsp;Nhung Thi Hong Dinh,&nbsp;Le Phuong Hoang Anh,&nbsp;Lan Thi Mai Dao,&nbsp;Van Dat Bui,&nbsp;Hong-Nhung Dao,&nbsp;Duc Son Le,&nbsp;Anh Thi Lan Ngo,&nbsp;Quang-Duong Le,&nbsp;Liem Nguyen Thanh","doi":"10.1002/mco2.70192","DOIUrl":"https://doi.org/10.1002/mco2.70192","url":null,"abstract":"<p>From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871610","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":"DEAD-Box Helicase 6 Blockade in Brain-Derived Aβ Oligomers From Alzheimer's Disease Patients Attenuates Neurotoxicity","authors":"Xiaoxu Wang,&nbsp;Lu Dai,&nbsp;Na Wu,&nbsp;Donghui Wu,&nbsp;Xinyuan Wang,&nbsp;Xia Meng,&nbsp;Qilei Zhang,&nbsp;Jing Lu,&nbsp;Xiaoxin Yan,&nbsp;Jing Zhang,&nbsp;Baian Chen","doi":"10.1002/mco2.70156","DOIUrl":"https://doi.org/10.1002/mco2.70156","url":null,"abstract":"<p>There are no effective curative treatments for Alzheimer's disease (AD), the most prevalent form of dementia. Amyloid-beta (Aβ) oligomers are considered key neurotoxic molecules that trigger AD. Recent studies have shown that direct antibody targeting of Aβ oligomers is beneficial for early AD patients; however, serious side effects (e.g., brain hemorrhage, edema, and shrinkage) persist. Considering that Aβ oligomers readily bind to other proteins, contributing to neurotoxicity and AD onset, those proteins could represent alternative therapeutic targets. However, proteins that bind to Aβ oligomers in the brains of AD patients have not yet been identified. In this study, we identified four proteins (DDX6, DSP, JUP, and HRNR) that bind to Aβ oligomers derived from the brains of AD patients. Intriguingly, among these four proteins, only the blockade of DEAD-box helicase 6 (DDX6) in human-derived Aβ oligomers attenuated their neurotoxicity both in vitro and in vivo. Mechanistic analysis revealed that DDX6 promotes the formation of Aβ oligomers, likely due to DDX6 bind to Aβ oligomers at four distinct sites. These findings suggest that DDX6 could serve as a potential therapeutic target to reduce the neurotoxicity of Aβ oligomers in the brain and prevent the progression of AD.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865748","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":"Midnolin Ubiquitination is Required for its Proteasome-Mediated Degradation","authors":"Jiang He,&nbsp;Tangmin Lai,&nbsp;Yuzu Zhao,&nbsp;Haonan Yang,&nbsp;Zheng Lei,&nbsp;Liu Zhou,&nbsp;Nan Li,&nbsp;Yu He,&nbsp;Wei Zhou,&nbsp;YongZhong Wu","doi":"10.1002/mco2.70189","DOIUrl":"https://doi.org/10.1002/mco2.70189","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;The ubiquitin–proteasome system (UPS) is responsible for protein degradation in cells, and proteins to be degraded usually need to be tagged with ubiquitin. Although the proteasome can also degrade proteins that are not tagged with ubiquitin [&lt;span&gt;1-5&lt;/span&gt;], its mechanism has not been fully elucidated. Some important proteins, such as p53, can be degraded through ubiquitin-independent pathways [&lt;span&gt;5&lt;/span&gt;], suggesting that ubiquitin-independent protein degradation may play a vital role in various biological processes. Midnolin (MIDN) has recently been reported to regulate the ubiquitin-independent proteasomal degradation of various immediate-early genes [&lt;span&gt;1&lt;/span&gt;], which play crucial roles in wound healing, immune cell activation, as well as neuronal adaptive responses, MIDN can capture proteins through its Catch domain and directly deliver substrates to the proteasome for degradation without substrate ubiquitination. However, whether MIDN can undergo ubiquitination and whether its ubiquitination affects its function remain unclear. Here, our results suggest that MIDN ubiquitination may be required for its proteasome-mediated degradation.&lt;/p&gt;&lt;p&gt;To explore the function of MIDN, we expressed exogenous Flag tagged MIDN in HEK-293T cells. We detected the ubiquitination of MIDN after immunoprecipitation using Flag beads, and the results indicated that MIDN is ubiquitinated (Figure 1A), suggesting that MIDN is also regulated by the UPS. Additionally, the ubiquitination level of MIDN significantly increased after treatment with MG132 (Figure 1A), indicating that MIDN ubiquitination may promote its proteasomal functions. However, it is not clear whether the ubiquitination of MIDN affects its proteasome-mediated degradation.&lt;/p&gt;&lt;p&gt;We then identified the ubiquitination sites of MIDN though global proteomic screening of lysine ubiquitination. First, we overexpressed MIDN in HEK-293T cells and subsequently treated them with MG132 for 6 h. Subsequently, the proteins were digested into peptides, and K-ε-GG peptides were enriched using anti-K-ε-GG antibodies (Figure 1B). Finally, liquid chromatography–mass spectrometry analysis revealed that a total of six ubiquitination sites on MIDN, K76, K84, K264, K354, K372, and K402, were ubiquitinated (Figure 1B).&lt;/p&gt;&lt;p&gt;To further investigate the function of MIDN ubiquitination, we constructed Flag tagged mutant proteins with mutations at K76, K84, K264, K354, K372, and K402 with arginine (R), as well as a mutant 6KR with simultaneous mutations at all six sites. We detected the ubiquitination level of each mutant in HEK-293T cells. The results suggested that the mutation of a single site did not significantly change the ubiquitination level of MIDN (Figure 1C). However, when six sites were mutated simultaneously, the ubiquitination level of MIDN was significantly reduced (Figure 1C). These results suggest that MIDN ubiquitination is not dominated by a single site, but may be coordinated","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871609","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}