MedComm最新文献

{"title":"Disruption of Spike Priming in Virus Entry: Tetrandrine as a Pan-Coronavirus Inhibitor","authors":"Kun Wang,&nbsp;Huiqiang Wang,&nbsp;Shuo Wu,&nbsp;Ge Yang,&nbsp;Haiyan Yan,&nbsp;Lijun Qiao,&nbsp;Xingqiong Li,&nbsp;Mengyuan Wu,&nbsp;Jiandong Jiang,&nbsp;Yuhuan Li","doi":"10.1002/mco2.70353","DOIUrl":"https://doi.org/10.1002/mco2.70353","url":null,"abstract":"<p>The emergence of novel and highly transmissible coronavirus (CoVs) highlights the urgent need for broad-spectrum antiviral agents. In our pursuit of effective treatments for coronavirus, we identified tetrandrine, the traditional Chinese medicine, as a pan-coronavirus inhibitor, exhibiting efficacy against HCoV-229E, HCoV-OC43, SARS-CoV-2, and its major variants of concern (VOCs), including alpha, beta, and omicron. Mechanistic investigations revealed that tetrandrine primarily targets the viral entry stage by binding to the Spike protein, disrupting its interaction with the host protease transmembrane serine protease 2 (TMPRSS2), and promoting Spike protein degradation, ultimately blocking the membrane fusion. Drug resistance selection study identified two mutations, G688R and D814Y, at S2 subunit of Spike, which reduced HCoV-229E's sensitivity to tetrandrine, supporting its direct action on the viral fusion machinery. Molecular docking and molecular dynamic (MD) simulation together with co-IP assay also verified the disruption of Spike-TMPRSS2 complex formation by tetrandrine. Importantly, tetrandrine treatment reduced viral load and mitigated neuropathological damage in infected neonatal mice. These findings establish tetrandrine as a broad-spectrum coronavirus entry inhibitor and offer mechanistic insights into its antiviral activity, providing a promising candidate for therapeutic development against current and future coronavirus threats.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923795","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":"Insulin-Like Growth Factor 2 mRNA Binding Protein 2 Promotes HBV-Associated Hepatocellular Carcinoma Progression by Enhancing Heme Oxygenase 1 Stability in an M6A-dependent Manner","authors":"Yan Zhao,&nbsp;Yan Cui,&nbsp;Hongxiu Qiao,&nbsp;Sandra Chiu,&nbsp;Xia Chuai","doi":"10.1002/mco2.70371","DOIUrl":"https://doi.org/10.1002/mco2.70371","url":null,"abstract":"<p>Dear Editor,</p><p>Chronic hepatitis B virus (HBV) infection has been established as a primary etiological factor in hepatocarcinogenesis. N6-methyladenosine (m⁶A), the predominant modification of eukaryotic RNAs, has been shown to play a critical role in both HBV life cycle and HBV-associated hepatocarcinogenesis [<span>1</span>]. This reversible modification exerts its biological effects through specialized RNA-binding proteins (“readers”) that specifically recognize m⁶A motifs and regulate RNA metabolism processes [<span>2</span>]. As a newly identified m⁶A reader, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) has been shown to promote tumorigenesis by enhancing the stability of its target transcripts [<span>3</span>]. Despite these findings, the role of IGF2BP2 in the specific pathogenesis of HBV-associated hepatocellular carcinoma (HCC) remains poorly understood. Therefore, our study aimed to systematically investigate the function of IGF2BP2 in HBV-associated hepatocarcinogenesis and evaluate its potential as a molecular target for HBV-associated HCC intervention.</p><p>First, we analyzed the correlation between the expression of IGF2BP2 and HBV-associated HCC (HBV-HCC). We collected liver tissue samples from HCC patients at the Third Hospital of Hebei Medical University (Hebei Province, China). The results revealed that the expression of IGF2BP2 in the liver tissue samples from both HCC groups was significantly higher than that in the paired adjacent normal tissue samples (Figure 1A). Additionally, the expression of IGF2BP2 in liver samples from the HBV-HCC group was also significantly higher than that in those from the HBV-negative group (Figure 1A). Furthermore, we detected the expression of IGF2BP2 in HBV-replicating HCC cells. The results demonstrated that the protein expression level of IGF2BP2 was also significantly elevated in HBV-replicating cells (Figure 1A).</p><p>Chronic HBV infection has been recognized as a major risk factor for HCC, and HBV-associated HCC is more aggressive than HCC caused by other factors [<span>4</span>]. To further clarify whether IGF2BP2 is involved in regulating the progression of HBV-HCC, we used a pCS-HBV1.3 plasmid-transfected HepG2 model to evaluate the effect of IGF2BP2 on the biological behavior of HBV-HCC. The results revealed that downregulating IGF2BP2 using shRNA significantly inhibited the proliferation, migration, and invasion capabilities of HBV-replicating HepG2 cells (Figure 1B). To further explore the role of IGF2BP2 in HCC progression in vivo, we performed xenograft tumor experiments by subcutaneously injecting shNC- or shIGF2BP2-transfected cells into nude mice (datails in Supplementary Information). We found that IGF2BP2 depletion significantly inhibited HCC growth, as reflected by reduced tumor volume and tumor weight (Figure 1C). In summary, these data demonstrate that IGF2BP2 promotes HBV-HCC progression.</p><p>Since sorafenib and ","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923819","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":"Programmed Cell Death in Cancer","authors":"Yuang Wei,&nbsp;William Hankey,&nbsp;Dongliang Xu,&nbsp;Fuwen Yuan","doi":"10.1002/mco2.70357","DOIUrl":"https://doi.org/10.1002/mco2.70357","url":null,"abstract":"<p>Cancer remains the most lethal disease globally, despite the significant progress made in early screening, surgery, and therapeutic development in recent decades. Programmed cell death (PCD) is a genetically regulated process essential for eliminating aberrant cells, yet its dysregulation drives tumorigenesis and therapy resistance. In this review, we present a complete discovery timeline of them and comprehensively synthesize the roles and mechanisms of major PCD forms, such as apoptosis, necroptosis, autophagy, pyroptosis, ferroptosis, and cuproptosis, across diverse cancer types. We not only detail the molecular mechanisms, dual functions, and alterations of these PCD modalities in cancers, but also summarize their interconnections and intrinsic crosstalk. Furthermore, we comprehensively discuss how diverse therapies, including chemotherapy, radiotherapy, immunotherapy, targeted agents, and hormone therapy, engage and manipulate specific PCD pathways, revealing the involvement of PCD in cancer treatment mechanisms. This review integrates extensive preclinical and clinical evidence on PCD-targeted therapies with an in-depth focus on ferroptosis, including its regulatory networks and therapeutic relevance. Special emphasis is placed on prostate cancer, highlighting the PCD-based translational opportunities in this common malignancy. Taken together, we provide novel insights into the complex interplay between PCD and cancer biology and offer a framework for developing precision oncology therapies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923379","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":"Epithelial–Mesenchymal Transition in Cancer: Insights Into Therapeutic Targets and Clinical Implications","authors":"Dhasarathdev Srinivasan,&nbsp;Ranjith Balakrishnan,&nbsp;Ankush Chauhan,&nbsp;Jeevan Kumar,&nbsp;Dinesh Murugan Girija,&nbsp;Reena Shrestha,&nbsp;Rupendra Shrestha,&nbsp;Rajasekaran Subbarayan","doi":"10.1002/mco2.70333","DOIUrl":"https://doi.org/10.1002/mco2.70333","url":null,"abstract":"<p>Radiation therapy is a fundamental component of cancer treatment, benefiting 50%–70% of patients by selectively targeting malignant tissues. However, radioresistance remains a significant challenge, often driven by epithelial–mesenchymal transition (EMT). EMT increases cancer invasiveness and metastasis by upregulating mesenchymal markers, including vimentin and N-cadherin, and downregulating epithelial markers, such as E-cadherin. EMT under radiation involves principal signaling pathways, including TGF-β, Wnt/β-catenin, Notch, and ERK, which regulate EMT through transcription factors such as Snail, Slug, Twist, and Zeb1/2. These alterations drive cytoskeletal reorganization, decrease cell–cell adhesion, and enhance extracellular matrix degradation via integrins, MMP-2, and MMP-9. We also explored how growth hormones, inflammatory cytokines, and hypoxia in the tumor microenvironment affect radiation-induced EMT. Targeting EMT pathways with monoclonal antibodies and small-molecule inhibitors of signaling pathways may help overcome radioresistance. However, due to the dual role of EMT in cancer progression and tissue regeneration, precise treatment strategies are essential. There is a lack of comprehensive multi-omics studies that provide insights into postradiation EMT progression. This review examines how radiation induces EMT and its impact on metastasis and immune responses while also proposing therapeutic approaches. Integrating EMT-targeting strategies with existing cancer treatments could enhance the effectiveness of radiotherapy and improve patient outcomes.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70333","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144914820","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":"Targeting the Hippo/YAP Pathway: A Promising Approach for Cancer Therapy and Beyond","authors":"Rajni Bala,&nbsp;Reecha Madaan,&nbsp;Onkar Bedi,&nbsp;Amrinder Singh,&nbsp;Ayushi Taneja,&nbsp;Renu Dwivedi,&nbsp;Gabriela Figueroa-González,&nbsp;Octavio Daniel Reyes-Hernández,&nbsp;Laura Itzel Quintas-Granados,&nbsp;Hernán Cortés,&nbsp;Dietrich Büsselberg,&nbsp;Gerardo Leyva-Gómez,&nbsp;Javad Sharifi-Rad,&nbsp;William C. Cho","doi":"10.1002/mco2.70338","DOIUrl":"https://doi.org/10.1002/mco2.70338","url":null,"abstract":"<p>Cancer represents a growing cause of death and a threat to public health worldwide; thus, there is an urgent need to understand its pathological mechanism and design effective therapies. The Hippo pathway regulates diverse cellular processes under physiological conditions; however, its dysregulation is associated with several types of cancer, including lung, pancreatic, colorectal, breast, and prostate cancer. Consequently, compounds targeting deregulated Hippo components represent potential treatments for a broad spectrum of cancers. Nonetheless, currently, there is limited information integrating the growing evidence of this potential. Therefore, the review's objective is to provide insight into the potential efficacy of targeting the Hippo/yes-associated protein (YAP) pathway for cancer therapy. First, we describe the molecular mechanisms of the Hippo signaling pathway in physiological conditions and several cancer types. We then provide an overview of natural products and synthetic compounds targeting this pathway, highlighting their potential applications in treating diverse cancers. We also discuss relevant preclinical and clinical studies of compounds targeting the Hippo pathway in cancer. Finally, we summarize our findings and offer recommendations for future research. This review emphasizes the role of the Hippo/YAP pathway in cancer and the potential of natural products and synthetic compounds targeting this pathway for cancer treatment.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144914986","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":"Phytosphingosine Alleviates Cigarette Smoke-Induced Bronchial Epithelial Cell Senescence in Chronic Obstructive Pulmonary Disease by Targeting the Free Fatty Acid Receptor 4","authors":"Yuan Zhan,&nbsp;Zhesong Deng,&nbsp;Ruonan Yang,&nbsp;Shanshan Chen,&nbsp;Jiaheng Zhang,&nbsp;Yating Zhang,&nbsp;Hao Fu,&nbsp;Qian Huang,&nbsp;Yiya Gu,&nbsp;Zhilin Zeng,&nbsp;Jinkun Chen,&nbsp;Jixian Zhang,&nbsp;Jixing Wu,&nbsp;Jungang Xie","doi":"10.1002/mco2.70345","DOIUrl":"https://doi.org/10.1002/mco2.70345","url":null,"abstract":"<p>Chronic obstructive pulmonary disease (COPD) is a complex and irreversible respiratory disorder with a poor prognosis and a lack of effective pharmaceutical treatment. Our previous metabolomics study identified phytosphingosine (PHS) as a key differential metabolite in COPD that is positively correlated with lung function. In this study, we investigated the bioactive effects of PHS on experimental COPD and its underlying mechanisms using cigarette smoke (CS)-induced mouse and cell models. We found that administering PHS improved CS-induced lung dysfunction, emphysema, and airway inflammation by reducing cellular senescence and the senescence-associated secretory phenotype in bronchial epithelium. Mechanistically, PHS interacted with the free fatty acid receptor 4 (FFAR4) and upregulated its expression, leading to the modulation of STIP1 homology and U-Box containing protein 1 (STUB1) downstream, which controlled the ubiquitination levels of P53 and mitigated cellular senescence. Moreover, both FFAR4 overexpression through intratracheal injection of adeno-associated virus and the administration of the FFAR4 agonist TUG891 showed therapeutic effects on CS-induced lung damage. Our results highlight the beneficial impacts of PHS in experimental COPD mediated through the FFAR4 receptor, protecting against CS-induced bronchial epithelial cell senescence and suggesting PHS as a promising therapeutic agent for COPD.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144914985","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":"Global Lactylome Reveals Lactylation-Dependent Mechanisms Underlying CXC Motif Chemokine Ligand 12 Expression in Pulmonary Endothelium During Acute Respiratory Distress Syndrome","authors":"Xu Liu,&nbsp;Haofei Wang,&nbsp;Weijie Ni,&nbsp;Xuecheng Dong,&nbsp;Mingzhu Zheng,&nbsp;Wei Chang","doi":"10.1002/mco2.70344","DOIUrl":"https://doi.org/10.1002/mco2.70344","url":null,"abstract":"<p>Acute respiratory distress syndrome (ARDS) is a life-threatening condition affecting millions of people worldwide. The severity of ARDS is associated with the dysfunction of pulmonary endothelial cells (PECs). Metabolic reprogramming is characterized by enhanced glycolysis and lactate accumulation, which play a critical role in this process. Here, we showed that lactate levels in the lungs of patients with ARDS were associated with disease severity and prognosis. Lactate promoted PEC dysfunction and drove experimental ARDS progression via lysine lactylation (Klac), a recently described posttranslational modification. Suppression of lactate-induced lactylation mitigated the development of ARDS and inhibited the release of chemokines, particularly CXC motif chemokine ligand 12 (CXCL12), from PECs. Through quantitative lactylome analysis, we identified hyperlactylation at K193 of Enolase 1 (Eno1), a glycolytic enzyme with RNA-binding capacity, as a previously unknown mechanism promoting CXCL12 production in PECs. Under homeostatic conditions, Eno1 could bind and inhibit the translation of CXCL12 mRNA, whereas increased glycolysis and accumulated lactate drove K193 hyperlactylation of Eno1 to release CXCL12 mRNA for accelerated translation. In addition, K193 hyperlactylation enhanced Eno1 enzymatic activity, further amplifying glycolysis. These findings establish Klac as a link between glycolytic reprogramming and PEC dysfunction, offering a new therapeutic target for ARDS.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144914984","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":"Hepatitis B Virus Assembly: Cryo-Electron Microscopy Reveals Structure of the Surface Antigen","authors":"Guobao Li,&nbsp;Jiaxin Cui,&nbsp;Jifeng Nie","doi":"10.1002/mco2.70348","DOIUrl":"https://doi.org/10.1002/mco2.70348","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Science&lt;/i&gt;, Wang et al. provided novel insights into the assembly of the hepatitis B virus (HBV) by utilizing cryo-electron microscopy (cryo-EM) [&lt;span&gt;1&lt;/span&gt;]. Through reconstruction of &lt;i&gt;D&lt;/i&gt;&lt;sub&gt;2&lt;/sub&gt;(222)- and &lt;i&gt;D&lt;/i&gt;&lt;sub&gt;4&lt;/sub&gt;(422)-like quasisymmetric subviral particles (SVPs) combined with near atomic-level determination of HBsAg topology, they elucidated how HBsAg dimers polymerize into higher-order architectures—enabling SVP formation and coordinated interactions with HBV nucleocapsids to assemble infectious virions.&lt;/p&gt;&lt;p&gt;The World Health Organization (WHO) estimates that approximately 254 million people were living with chronic hepatitis B in 2022. Viral hepatitis caused 1.3 million deaths globally, with HBV accounting for 83% of the fatalities. As a member of the &lt;i&gt;Hepadnaviridae&lt;/i&gt; family, HBV generates non-infectious spherical SVPs (17–22 nm in diameter), filamentous SVPs (22 nm in diameter), and infectious Dane particles (∼44 nm in diameter) during its life cycle. Notably, SVPs can outnumber Dane particles by up to 10,000-fold, contributing to immune tolerance and the persistence of chronic infection. Deciphering the architecture and assembly of HBV particles remains crucial for understanding viral morphogenesis. However, the acquisition of SVPs and their HBsAg-mediated structural heterogeneity present significant barriers to high-resolution structural elucidation of distinct SVP subtypes. Elucidating HBsAg conformation is essential for rational vaccine design, neutralizing epitope mapping, and HBV therapeutics development.&lt;/p&gt;&lt;p&gt;HBsAg is translated from a single open reading frame encoding three co-terminal isoforms: small (S-), medium (M-), and large (L-) HBsAg (Figure 1A). Among these, S-HBsAg constitutes the predominant component in both SVPs and infectious Dane particles. Wang et al. expressed S-HBsAg in human embryonic kidney 293 (HEK293) and Chinese hamster ovary (CHO) cells, generating SVPs morphologically analogous to native virions. HEK293-derived SVPs were purified by affinity chromatography, whereas CHO-derived SVPs were isolated via sucrose gradient centrifugation. Both populations underwent size-exclusion chromatography to exclude aggregates and isolate monodisperse particles, ensuring sample homogeneity for cryo-EM. After data acquisition and analysis, two monodisperse populations of quasi-spherical SVPs with a diameter of 22 nm were identified. Single-particle reconstruction revealed two distinct icosahedral symmetry classes: &lt;i&gt;D&lt;/i&gt;&lt;sub&gt;2&lt;/sub&gt;(222) and &lt;i&gt;D&lt;/i&gt;&lt;sub&gt;4&lt;/sub&gt;(422) (referred to as “D2” and “D4,” respectively). By applying symmetry constraints and a custom orientation transformation script, the authors achieved a 3.7 Å resolution structure of S-HBsAg. It comprises two N-terminal transmembrane α-helices (TH1 and TH2) and four C-terminal membrane-embedded α-helices (EH1–EH4) (Figure 1B). The protein integrates into the lipid bilayer with the cytoplasmic lo","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910088","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":"Chimeric Antigen Receptor-Macrophage Therapy Enters the Clinic: The First-in-Human Trial for HER2+ Solid Tumors","authors":"Wenxue Ma,&nbsp;Catriona Jamieson","doi":"10.1002/mco2.70374","DOIUrl":"https://doi.org/10.1002/mco2.70374","url":null,"abstract":"&lt;p&gt;In a recent study published in Nature Medicine (2025), Reiss et al. [&lt;span&gt;1&lt;/span&gt;] reported the first-in-human Phase 1 trial of CT-0508, a chimeric antigen receptor macrophage (CAR-M) therapy targeting HER2-overexpressing solid tumors. This trial demonstrated safety, feasibility, and early immune activity in heavily pretreated patients, marking the first clinical validation of macrophage-based immunotherapy. This milestone highlights the potential of engineered macrophages to overcome tumor microenvironment (TME)-mediated resistance, signaling a paradigm shift for treating solid tumors refractory to current therapies.&lt;/p&gt;&lt;p&gt;Fourteen patients with HER2-overexpressing tumors, including breast, gastroesophageal, and salivary duct carcinomas, were enrolled and received CT-0508 without prior lympho-depleting chemotherapy. Two dosing regimens were explored: fractionated (Group 1) and bolus (Group 2). CAR-Ms were generated from autologous monocytes using a replication-incompetent adenoviral vector (Ad5.F35), achieving high viability, purity, and CAR expression across all manufactured products. Preclinical assays demonstrated HER2-specific cytotoxicity, phagocytosis, and secretion of proinflammatory cytokines upon antigen engagement.&lt;/p&gt;&lt;p&gt;Clinically, CT-0508 exhibited a favorable safety profile. No dose-limiting toxicities, Grade ≥3 cytokine release syndrome (CRS), or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Grade 1–2 CRS occurred in nine patients and was managed without corticosteroids or intensive supportive care. Importantly, the trial avoided the use of lympho-depleting regimens such as cyclophosphamide or fludarabine, which are standard in CAR-T therapies, thereby supporting a more tolerable, outpatient-based delivery model. This distinction represents a major advantage in the solid tumor space, where toxicity concerns and logistical burdens have limited broader access to cell therapy.&lt;/p&gt;&lt;p&gt;Although no objective responses (per RECIST v1.1) were observed, four of nine patients (44.5%) with HER2 immunohistochemistry (IHC) 3&lt;sup&gt;+&lt;/sup&gt; tumors achieved stable disease (SD), while all five patients with HER2 IHC 2&lt;sup&gt;+&lt;/sup&gt; tumors exhibited progressive disease (PD). Tumor volume reductions were noted in 41% of measurable lesions, and circulating tumor DNA (ctDNA) levels decreased in 62% of patients, including all those with SD. These molecular and radiographic evidence indicate biological activity, although transient. Interestingly, some patients exhibited ctDNA rebound at later timepoints, raising questions about the durability of response and the potential need for maintenance dosing or sequential therapeutic strategies. These observations reinforce the value of integrating longitudinal molecular monitoring in early-phase trials to better understand the kinetics of response and identify early markers of relapse. A graphical overview summarizing the clinical workflow, immunologic changes, and future directio","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70374","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910089","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":"Mitochondrial Dysfunction in Neurodegenerative Diseases","authors":"Chongyang Chen,&nbsp;Yujie Zhao,&nbsp;Jing Wang,&nbsp;Donghui Pan,&nbsp;Xinyu Wang,&nbsp;Yuping Xu,&nbsp;Junjie Yan,&nbsp;Lizhen Wang,&nbsp;Xifei Yang,&nbsp;Ming Lu,&nbsp;Gong-Ping Liu","doi":"10.1002/mco2.70326","DOIUrl":"https://doi.org/10.1002/mco2.70326","url":null,"abstract":"<p>Mitochondria are indispensable for the normal physiological activities and metabolism of living organisms. The proper function of mitochondria in the brain is crucial for maintaining the normal brain function with high energy demands. There are growing evidences that mitochondrial dysfunction plays a critical role in multiple of neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. In this review, the research progress and future development trajectory of mitochondrial function in NDDs will be comprehensively summarized, which focusing on mitochondrial physiological function, the mechanisms underlying mitochondrial dysfunction in diverse NDDs, research approaches for exploring mitochondrial function, various strategies for targeted mitochondrial therapy, and the challenges and opportunities encountered in the evaluation of mitochondrial-targeted therapeutic drugs. The feasibility of in vivo mitochondrial imaging and the future perspectives of AI for mitochondria-targeted drug screening are deliberated, which will facilitate the advancement of the comprehension of mitochondrial functional mechanisms in NDDs and the development of future clinical therapeutic drugs. This review shall furnish several insights regarding novel research methodologies and drug developments for researchers engaged in the investigation of mitochondrial dysfunction in NDDs.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 9","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910087","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}