MedComm最新文献

{"title":"Cryo-EM Structures Reveal Key Mechanisms of Noradrenaline Transporter","authors":"Peng Su, Mao Li, Fangfang Zhou","doi":"10.1002/mco2.70188","DOIUrl":"https://doi.org/10.1002/mco2.70188","url":null,"abstract":"<p>In a recent article in <i>Nature</i>, Hu et al. [<span>1</span>] unveiled cryo-EM (cryo-electron microscopy) structures of the human noradrenaline transporter (NET) in multiple states—unbound (<i>apo)</i>, substrate-bound (noradrenaline), and bound with several clinically used drugs (Figure 1A). These structures, captured in inward- and outward-facing conformations, shed light on the substrate transport and inhibition mechanisms of NET.</p><p>The noradrenaline system, dependent on noradrenaline as its primary neurotransmitter, regulates essential physiological functions, including mood, pain perception, sleep-wake cycle, arousal, attention, feeding behavior, and fight-or-flight responses [<span>2</span>]. Noradrenaline system dysfunction is implicated in several mental disorders. NET, located in presynaptic neurons, mediates noradrenaline reuptake, effectively terminating synaptic signaling and modulating neurotransmitter levels. Given the crucial role of NET in maintaining noradrenaline homeostasis, it has emerged as a primary target for the treatment of mental health disorders, including depression, attention deficit hyperactivity disorder, and neuropathic pain. Clinically used drugs exert their effects by targeting NET. However, the detailed molecular mechanisms underlying the effects of these inhibitors remain unclear. In addition, fundamental questions regarding the transport mechanism of NET, such as ligand and ion coupling and the conformational transition across functional states, remain elusive.</p><p>To elucidate the mechanisms underlying NET transport and inhibition, Hu et al. [<span>1</span>] expressed human NET and reconstituted it into nanodiscs to comprehensively replicate the native membrane environment. Using cryo-EM, they obtained structures at 2.6 Å of NET in <i>apo</i> and noradrenaline-bound states, capturing the transporter in inward- and outward-facing conformations. NET operates as a secondary active transporter that leverages electrochemical gradients of sodium and chloride ions. The high-resolution maps facilitated the precise localization of sodium and chloride ion-binding sites, highlighting their roles in the transport cycle of NET. In addition to the primary binding site, Hu et al. [<span>1</span>] identified a secondary substrate-binding site within the extracellular cavity that existed only in the inward-facing conformation. Upon mutating key residues, including R301 and E382, which interact with noradrenaline at this site, they observed a partial reduction in the transport activity for the E382A mutant, whereas the R301A mutation did not appear to affect transport activity. This finding suggests that the secondary site is complementary in modulating substrate dynamics, potentially influencing the efficiency and regulation of noradrenaline transport under physiological conditions. By resolving the structure of NET in both outward- and inward-facing conformations, they mapped the structural rearrangements essenti","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70188","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831320","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":"Expanding the Scope of Molecular Glues: TRIM21 as a Multimeric Protein Degrader","authors":"Kai Huang, Anqi Zhou, Xiangxiang Zhou","doi":"10.1002/mco2.70178","DOIUrl":"https://doi.org/10.1002/mco2.70178","url":null,"abstract":"<p>In a recent study published on <i>Cell</i>, Lu et al. [<span>1</span>] introduce a novel targeted protein degradation (TPD) strategy that employs Tripartite motif-containing protein 21 (TRIM21), an E3 ligase activated through clustering, to achieve multimeric protein degradation with remarkable selectivity.</p><p>The field of TPD has expanded rapidly with the development of molecular glues (MGs) and proteolysis-targeting chimeras (PROTACs), which use E3 ubiquitin ligases to tag proteins for degradation [<span>2</span>]. However, current TPD methods rely heavily on E3 ligases such as Cereblon and Von Hippel–Lindau tumor suppressor, which are broadly expressed and lack conditional activity, posing challenges for selective targeting, especially in complex protein assemblies [<span>3</span>].</p><p>An additional challenge lies in selectively targeting multimeric proteins, which are often implicated in disease due to their aggregated forms, as seen in neurodegenerative disorders and certain cancers. Current TPD strategies typically lack the ability to distinguish between monomeric and multimeric forms of a protein, resulting in potential off-target effects and limited efficacy for diseases marked by aberrant multimerization. These limitations have highlighted the need for degraders that can selectively target multimeric assemblies with minimal impact on their monomeric counterparts, which may retain essential cellular functions.</p><p>The study focuses on (S)-ACE-OH, a metabolite derived from the antipsychotic acepromazine, which acts as a MG facilitating interaction between TRIM21 and the nuclear pore protein NUP98, leading to selective degradation of multimeric protein structures within the nuclear pore complex (NPC) (Figure 1). Specifically, the authors demonstrate that treatment with (S)-ACE-OH leads to the depletion of NPC subunits, as evidenced by proteomics analyses and transmission electron microscopy, which reveal structural disintegration of the inner NPC ring.</p><p>The researchers first identify (S)-ACE-OH as a MG that mediates an interaction between TRIM21 and NUP98, a protein critical to the integrity of the NPC. Using CRISPR-based screening, the authors confirmed TRIM21 as essential for the cytotoxic effects of (S)-ACE-OH, particularly under interferon-gamma conditions, which induce TRIM21 expression. Through a competitive cell growth assay in interferon-gamma-stimulated cancer cell lines, they observed that (S)-ACE-OH selectively targets multimeric NUP98-containing complexes, reducing cell viability by degrading the NPC's inner ring. Proteomic quantification demonstrated a significant reduction in NUP98 levels, underscoring the compound's potency. The work highlights how multimeric proteins, but not monomeric counterparts, induce the clustering of TRIM21, a mechanism necessary for activating TRIM21's E3 ligase function. This clustering-dependent activation serves as a unique mechanism for selectively degrading multimeric protein ass","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 5","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831131","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":"Genomic and Immune Profiling of Esophageal Squamous Cell Carcinoma Undergoing Neoadjuvant Therapy Versus Upfront Surgery Identifies Novel Immunogenic Cell Death-Based Signatures for Predicting Clinical Outcomes","authors":"Peidong Song,&nbsp;Wenze Tian,&nbsp;Yujia Zheng,&nbsp;Sukai Xu,&nbsp;Zihao Hu,&nbsp;Xing Jin,&nbsp;Xuejuan Zhu,&nbsp;Lijie Tan,&nbsp;Donglai Chen,&nbsp;Yongbing Chen","doi":"10.1002/mco2.70171","DOIUrl":"https://doi.org/10.1002/mco2.70171","url":null,"abstract":"<p>It remains undetermined regarding the impact of neoadjuvant therapy on immunogenic cell death (ICD) and subsequent tumor microenvironment (TME) remodeling in esophageal squamous cell carcinoma (ESCC). And it is of paramount significance to identify beneficiaries from neoadjuvant therapy in treatment-naïve ESCC. In this study, 88 ESCC samples undergoing neoadjuvant therapy plus surgery (NA+S) or surgery alone (SA) were subjected to bulk-RNA sequencing. A five-gene RINscore incorporating ICD-related signature genes with TME-based hub genes was established to predict clinical outcomes and pharmacological responses, in which SLAMF7 and IL1R1 were selected out as co-expressed genes. The regulatory mechanism of the repressive co-transcription factor BATF of SLAMF7 and IL1R1 was further demonstrated. Our data demonstrated that NA+S led to high abundance in kinds of T helper cells, nature killer T cells and M1-like macrophages with increased CD8+T cells infiltration compared with SA. ICD phenotypes were further characterized in treatment-naïve ESCC to determine their differences in TME and potential benefits from NA. Our findings not only offered novel insights into the distinct TME and ICD profiles of ESCC undergoing different therapeutic modes, but also provided the RINscore, which may aid oncologists in determining individualized (neo)adjuvant immunotherapy regimen.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762149","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":"Pancreatic Cancer: Pathogenesis and Clinical Studies","authors":"Kexun Zhou,&nbsp;Yingping Liu,&nbsp;Chuanyun Tang,&nbsp;Hong Zhu","doi":"10.1002/mco2.70162","DOIUrl":"https://doi.org/10.1002/mco2.70162","url":null,"abstract":"<p>Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS–MAPK, PI3K–AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody–drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762148","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":"Posttranslational Modification in Bone Homeostasis and Osteoporosis","authors":"Yuzhe Lin,&nbsp;Shide Jiang,&nbsp;Yuming Yao,&nbsp;Hengzhen Li,&nbsp;Hongfu Jin,&nbsp;Guang Yang,&nbsp;Bingzhou Ji,&nbsp;Yusheng Li","doi":"10.1002/mco2.70159","DOIUrl":"https://doi.org/10.1002/mco2.70159","url":null,"abstract":"<p>Bone is responsible for providing mechanical protection, attachment sites for muscles, hematopoiesis micssroenvironment, and maintaining balance between calcium and phosphorate. As a highly active and dynamically regulated organ, the balance between formation and resorption of bone is crucial in bone development, damaged bone repair, and mineral homeostasis, while dysregulation in bone remodeling impairs bone structure and strength, leading to deficiency in bone function and skeletal disorder, such as osteoporosis. Osteoporosis refers to compromised bone mass and higher susceptibility of fracture, resulting from several risk factors deteriorating the balanced system between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. This balanced system is strictly regulated by translational modification, such as phosphorylation, methylation, acetylation, ubiquitination, sumoylation, glycosylation, ADP-ribosylation, S-palmitoylation, citrullination, and so on. This review specifically describes the updating researches concerning bone formation and bone resorption mediated by posttranslational modification. We highlight dysregulated posttranslational modification in osteoblast and osteoclast differentiation. We also emphasize involvement of posttranslational modification in osteoporosis development, so as to elucidate the underlying molecular basis of osteoporosis. Then, we point out translational potential of PTMs as therapeutic targets. This review will deepen our understanding between posttranslational modification and osteoporosis, and identify novel targets for clinical treatment and identify future directions.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741399","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":"Bending and Scission: When the Membraneless Condensates Meet Endosome Membrane","authors":"Zhengkun Zhang,&nbsp;Feng Xie,&nbsp;Long Zhang","doi":"10.1002/mco2.70165","DOIUrl":"https://doi.org/10.1002/mco2.70165","url":null,"abstract":"&lt;p&gt;In a recent study reported in &lt;i&gt;Nature&lt;/i&gt;, Xiaofeng Fang's group from Tsinghua University and a team led by Roland Knorr from the University of Cologne in Germany discovered that the plant protein FREE1 can form condensates through phase separation, which drive endosomal membrane invagination and instability via wetting phenomenon [&lt;span&gt;1&lt;/span&gt;]. This study highlights biomolecular condensates' critical role in physiological processes, particularly in mediating endosomal sorting complex required for transport (ESCRT) and adenosine triphosphate (ATP) independent intraluminal vesicle (ILV) formation.&lt;/p&gt;&lt;p&gt;Multivesicular bodies (MVBs) are vital organelles within cells that are primarily responsible for delivering cargo molecules from the endocytic pathway to lysosomes for degradation and recycling and for regulating biological processes such as nutrient uptake, immunity, and signal transduction [&lt;span&gt;2&lt;/span&gt;]. The MVB membrane forms ILVs through invagination and scission; these ILVs then sort protein cargo and require the consumption of ATP by the ESCRT protein complex. Biomolecular condensates result from liquid–liquid phase separation (LLPS) and typically exhibit the characteristics of liquid droplets or gel-like aggregates, performing various functions within cells. Previous studies have shown that condensates interact with membranes, leading to “wetting” and capillary phenomena. However, the biological significance of wetting-related capillary forces in cellular processes remains largely unknown [&lt;span&gt;3&lt;/span&gt;]. In the study led by Xiaofeng Fang and colleagues, the authors used in vitro reconstitution, computer simulations, and genetic experimental analysis to discover that FREE1 condensates can induce membrane curvature and invagination independently of the ESCRT protein complex and ATP. Notably, the ATP-independent membrane scission mediated by FREE1 condensates was primarily supported by in vitro reconstitution and computer simulations, whereas the genetic experimental analysis (e.g., vps2.1 knockout complementation) indirectly supports ESCRT-independence. The study first used biotinylated isoxazole (b-isox) compounds to precipitate and screen proteins with phase-separation capabilities [&lt;span&gt;4&lt;/span&gt;], revealing that FREE1 possesses robust phase-separation abilities both in vivo and in vitro. This phase separation ability is unaffected by salt concentration, and the intrinsically disordered region (IDR) at the N-terminus of FREE1 is required for phase separation. In addition, FREE1 contains an FYVE domain capable of binding to the membrane lipid phosphatidylinositol 3-phosphate (PI3P), enabling its localization to the MVB membrane. Further research revealed that the formation of condensates significantly enhances the membrane-binding capacity of FREE1. Moreover, FREE1 condensates served as scaffolds, recruiting other ESCRT components, particularly the ESCRT-I subcomplex (including VPS23, VPS28, and VPS37), as client molecules into","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741328","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":"Dynamic Alterations in DNA Methylation of CD4+ T Cells and Macrophages in a Murine Model of Tuberculous Pleural Infection Induced by BCG Vaccination","authors":"Ming-Ming Shao,&nbsp;Qing-Yu Chen,&nbsp;Xin Zhang,&nbsp;Shu-Feng Dong,&nbsp;Rui-Qi Wei,&nbsp;Huan-Zhong Shi,&nbsp;Feng-Shuang Yi","doi":"10.1002/mco2.70166","DOIUrl":"https://doi.org/10.1002/mco2.70166","url":null,"abstract":"<p>Tuberculous pleural effusion (TPE) is a prevalent form of extrapulmonary tuberculosis, and immune abnormalities play a crucial role in promoting its development. However, the dynamic changes and regulatory characteristics of immune cells during TPE progression remain incompletely understood. This study analyzed DNA methylation and transcriptome data from macrophages and CD4⁺ T cells from pleural lavage fluid of BCG-induced tuberculous pleurisy mouse models at specific time points (Days 0, 1, 7, and 14). The results revealed substantial alterations in DNA methylation patterns associated with inflammatory factors and interferon genes. Notably, macrophages exhibited the most pronounced differences in DNA methylation profiles on Day 1, while CD4⁺ T cells demonstrated gradual changes over time. The investigation further indicated that DNA methylation primarily regulated the differentiation of Th1, Th17, and Th22 cells but not Th9 cells. Additionally, single-cell RNA sequencing analysis revealed an increasing expression of C1q during infection, which was regulated by DNA methylation. Importantly, C1q⁺ and C1q⁻ macrophages demonstrated distinct roles in modulating immune responses during infection. This research provides valuable insights into the DNA methylation profile of immune cells during <i>Mycobacterium bovis</i> infection–induced pleurisy in a mouse model, enhancing our understanding of the upstream regulatory mechanisms underlying immune response development in TPE.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741396","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":"STAT3 Signaling Pathway in Health and Disease","authors":"Md Abdus Samad,&nbsp;Iftikhar Ahmad,&nbsp;Aakifah Hasan,&nbsp;Mohammad Hassan Alhashmi,&nbsp;Arusha Ayub,&nbsp;Fahad A. Al-Abbasi,&nbsp;Ajoy Kumer,&nbsp;Shams Tabrez","doi":"10.1002/mco2.70152","DOIUrl":"https://doi.org/10.1002/mco2.70152","url":null,"abstract":"<p>Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor involved in multiple physiological and pathological processes. While STAT3 plays an essential role in homeostasis, its persistent activation has been implicated in the pathogenesis of various diseases, particularly cancer, bone-related diseases, autoimmune disorders, inflammatory diseases, cardiovascular diseases, and neurodegenerative conditions. The interleukin-6/Janus kinase (JAK)/STAT3 signaling axis is central to STAT3 activation, influencing tumor microenvironment remodeling, angiogenesis, immune evasion, and therapy resistance. Despite extensive research, the precise mechanisms underlying dysregulated STAT3 signaling in disease progression remain incompletely understood, and no United States Food and Drug Administration (USFDA)-approved direct STAT3 inhibitors currently exist. This review provides a comprehensive evaluation of STAT3's role in health and disease, emphasizing its involvement in cancer stem cell maintenance, metastasis, inflammation, and drug resistance. We systematically discuss therapeutic strategies, including JAK inhibitors (tofacitinib, ruxolitinib), Src Homology 2 domain inhibitors (S3I-201, STATTIC), antisense oligonucleotides (AZD9150), and nanomedicine-based drug delivery systems, which enhance specificity and bioavailability while reducing toxicity. By integrating molecular mechanisms, disease pathology, and emerging therapeutic interventions, this review fills a critical knowledge gap in STAT3-targeted therapy. Our insights into STAT3 signaling crosstalk, epigenetic regulation, and resistance mechanisms offer a foundation for developing next-generation STAT3 inhibitors with greater clinical efficacy and translational potential.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741588","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":"Restoration of Transgelin 2 Expression Reverses Immune Escape in Ovarian Cancer: A Dawn for Immunotherapy","authors":"Zhiqiang Wang,&nbsp;Ge Lou,&nbsp;Mingzhu Yin","doi":"10.1002/mco2.70164","DOIUrl":"https://doi.org/10.1002/mco2.70164","url":null,"abstract":"&lt;p&gt;In a seminal study published in &lt;i&gt;Nature&lt;/i&gt;, Hwang et al. recently revealed for the first time that Transgelin 2 (TAGLN2) regulates lipid metabolism and antitumor function through interaction with fatty acid binding protein 5 (FABP5) in CD8+ T cells [&lt;span&gt;1&lt;/span&gt;]. The mechanism by which TAGLN2 is inhibited by endoplasmic reticulum (ER) stress in the microenvironment of ovarian cancer (OC) leading to T-cell dysfunction was clarified, providing a new target and a potential strategy for improving immunotherapy for solid tumors.&lt;/p&gt;&lt;p&gt;Lipid metabolism plays an indispensable role in the activation, proliferation, and execution of effector functions in T cells [&lt;span&gt;2&lt;/span&gt;]. As a critical regulator of lipid metabolism, FABP5 efficiently coordinates lipid uptake and transport, providing sufficient energy substrates for mitochondrial respiration in T cells, thereby ensuring their optimal bioenergetic status during antitumor immunity [&lt;span&gt;3, 4&lt;/span&gt;]. However, significant gaps remain in understanding the regulatory mechanisms of FABP5 in T-cell lipid metabolism, particularly within tumor-related contexts. Metastatic OC, a refractory immunosuppressive tumor resistant to multiple therapeutic approaches—including T cell-based immunotherapies, exerts a microenvironment that drives functional impairment in tumor-infiltrating T cells [&lt;span&gt;5&lt;/span&gt;]. Consequently, elucidating the molecular mechanisms underlying immune evasion in OC and identifying potential therapeutic targets capable of reversing T cell dysfunction is paramount for enhancing the efficacy of OC immunotherapy and improving patient prognosis.&lt;/p&gt;&lt;p&gt;The exact way tumor microenvironment (TME) inhibits T cell lipid metabolism is unclear. Hwang et al. demonstrated that TAGLN2 expression in CD8+ T cells was significantly downregulated in both ascites and solid tumors of OC patients. In addition, CD8+ T cell surface FABP5 expression was decreased in ascites from OC patients compared to peripheral CD8+ T cells from cancer-free individuals, although total intracellular FABP5 levels were comparable. These results suggest that the OC microenvironment may affect the lipid metabolism and function of intratumoral T cells by repressing TAGLN2 expression. Further experiments showed that the interaction of TAGLN2 with FABP5 is critical for the localization and function of FABP5 on the surface of activated CD8+ T cells. This allows the cells to efficiently take up extracellular fatty acids to fuel mitochondrial respiration, thereby maintaining the energy requirements of CD8+ T cells. These results emphasize the central role of TAGLN2 in T-cell lipid metabolism, particularly in promoting FABP5-mediated lipid uptake.&lt;/p&gt;&lt;p&gt;What molecular pathways link TME stress signals to TAGLN2 suppression?​ The authors discovered that the ER stress response inhibits TAGLN2 expression through the IRE1α-XBP1s signaling pathway. The active form of XBP1s can bind directly to the promoter region of the &lt;i&gt;TAGLN2&lt;/i&gt; ge","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741589","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":"Transforming Growth Factor Beta2 Promotes Migration and Inhibits the Proliferation of Gastric Cancer Cells by Regulating the pSmad2/3-NDRG1 Signaling Pathway","authors":"Feng-Jun He,&nbsp;Xiao-Long Chen,&nbsp;Yun-Feng Zhu,&nbsp;Hua-Yang Pang,&nbsp;Ze-Dong Li,&nbsp;Pan-Ping Liang,&nbsp;Tao Jin,&nbsp;Zheng-Wen Chen,&nbsp;Ze-Hua Chen,&nbsp;Jian-Kun Hu,&nbsp;Kun Yang","doi":"10.1002/mco2.70148","DOIUrl":"https://doi.org/10.1002/mco2.70148","url":null,"abstract":"<p>Transforming growth factor beta2 (TGFβ2) is upregulated in gastric cancer (GC), playing a crucial role in driving its progression. However, the biological effects of TGFβ2 in GC metastasis and proliferation remain not fully understood. Our study reveals that TGFβ2 enhances N-myc downstream-regulated gene 1 (NDRG1) protein expression by activating the TGFβR/Smad2/3-dependent pathway, accelerating GC progression. TGFβ2 knockdown downregulates NDRG1 by inhibiting the TGFβR/Smad2/3 signaling pathway, which in turn inhibits GC cell migration and epithelial–mesenchymal transition (EMT) but stimulates proliferation. Both TGFβ2 upregulation and NDRG1 upregulation enhance GC cell migration in vitro and promote lung metastasis in mouse models. Interfering with NDRG1 reverses TGFβ2-induced migration, and inhibiting Smad2/3 or TGFβR reverses TGFβ2-induced NDRG1 upregulation and GC cell migration. Clinical sample analysis shows high TGFβ2 and NDRG1 expression in GC, associated with poor prognosis. Our study reveals that TGFβ2 upregulates NDRG1 via the TGFβR/Smad2/3 pathway, driving GC progression and highlighting the potential role of the TGFβ2NDRG1 axis in GC-targeted therapies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 4","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717164","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}