Biomolecules最新文献

{"title":"Modulation of Kv Channel Gating by Light-Controlled Membrane Thickness.","authors":"Rohit Yadav, Juergen Pfeffermann, Nikolaus Goessweiner-Mohr, Toma Glasnov, Sergey A Akimov, Peter Pohl","doi":"10.3390/biom15050744","DOIUrl":"10.3390/biom15050744","url":null,"abstract":"<p><p>Voltage-gated potassium (Kv) channels are e ssential for shaping action potentials and rely on anionic lipids for proper gating, yet the mechanistic basis of lipid-channel interactions remains unclear. Cryo-electron microscopy studies suggest that, in the down state, arginine residues of the voltage sensor draw lipid phosphates upward, leading to a local membrane thinning of ~5 Å-an effect absent in the open state. To test whether membrane thickness directly affects voltage sensor function, we reconstituted Kv channels from <i>Aeropyrum pernix</i> (KvAP) into planar lipid bilayers containing photoswitchable lipids. Upon blue light illumination, the membrane thickened, and KvAP activity increased; UV light reversed both effects. Our findings indicate that membrane thickening weakens the interaction between lipid phosphates and voltage-sensing arginines in the down state, lowering the energy barrier for the transition to the up state and thereby promoting channel opening. This non-genetic, membrane-mediated approach provides a new strategy to control ion channel activity using light and establishes a direct, reversible link between membrane mechanics and voltage sensing, with potential applications in the remote control of neuronal excitability.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Analysis of HRD Assay Variability in High-Grade Serous Ovarian Cancer: Impacts of BRCA1/2 Mutation Subtypes on HRD Assessment.","authors":"Giovanni Luca Scaglione, Valentina Lombardo, Maurizio Polano, Giuseppa Scandurra, Angela Pettinato, Corrado Giunta, Rosario Iemmolo, Paolo Scollo, Ettore D Capoluongo","doi":"10.3390/biom15050745","DOIUrl":"10.3390/biom15050745","url":null,"abstract":"<p><p>The HRD (Homologous Recombination Deficiency) test is considered a genomic alteration useful for guiding therapeutic decisions in patients with ovarian cancer. Some commercial and in house alternative \"academic\" tests are available. Recent findings indicate that not all <i>BRCA1/2</i> mutations determine the magnitude of HRD and that some patients carrying <i>BRCA1/2</i> mutations may exhibit indeterminate or even negative HRD scores. Furthermore, certain therapies (e.g., olaparib and bevacizumab) offer particularly pronounced benefits for high-grade serous ovarian cancer (HGSOC) patients harboring mutations in the DNA-binding domain (DBD) of <i>BRCA1/2</i>. The aim of the present study is to investigate the relationship between the HRD scores and <i>BRCA1/2</i> status of 51 HGSOC patients (50 <i>BRCA1/2</i> mutated and 1 wild type). The HRD status was assessed by means of shallow whole-genome sequencing and <i>BRCA1/2</i> status by the NGS pipeline. We did not find a correlation between the HRD status and type of <i>BRCA1/2</i> alterations. A strong correlation between the HRD score and age was found. Our paper underlines the need to introduce other biological factors within the algorithms of the HRD evaluation in order to better tailor the HRD status, harmonize the metrics of the HRD assessment, and personalize therapies.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12110076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomics-Based Profiling of the Fecal Microbiome Reveals Potential Disease-Specific Signatures in Pediatric IBD (PIBD).","authors":"Anita H DeSantis, Kristina Buss, Keaton M Coker, Brad A Pasternak, Jinhua Chi, Jeffrey S Patterson, Haiwei Gu, Peter W Jurutka, Todd R Sandrin","doi":"10.3390/biom15050746","DOIUrl":"10.3390/biom15050746","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD), which includes Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic gastrointestinal (GI) disorder affecting 1 in 100 people in the United States. Pediatric IBD (PIBD) is estimated to impact 15 per 100,000 children in North America. Factors such as the gut microbiome (GM), genetic predisposition to the disease, and certain environmental factors are thought to be involved in pathogenesis. However, the pathophysiology of IBD is incompletely understood, and diagnostic biomarkers and effective treatments, particularly for PIBD, are limited. Recent work suggests that these factors may interact to influence disease development, and multiomic approaches have emerged as promising tools to elucidate the pathophysiology. We employed metagenomics, metabolomics- and metatranscriptomics-based approaches to examine the microbiome, its genetic potential, and its activity to identify factors associated with PIBD. Metagenomics-based analyses revealed pathways such as octane oxidation and glycolysis that were differentially expressed in UC patients. Additionally, metatranscriptomics-based analyses suggested enrichment of glycan degradation and two component systems in UC samples as well as protein processing in the endoplasmic reticulum, ribosome, and protein export in CD and UC samples. In addition, metabolomics-based approaches revealed patterns of differentially abundant metabolites between healthy and PIBD individuals. Interestingly, overall microbiome community composition (as measured by alpha and beta diversity indices) did not appear to be associated with PIBD. However, we observed a small number of differentially abundant taxa in UC versus healthy controls, including members of the Classes <i>Gammaproteobacteria</i> and <i>Clostridia</i> as well as members of the Family <i>Rikenellaceae</i>. Accordingly, when identifying potential biomarkers for PIBD, our results suggest that multiomics-based approaches afford enhanced potential to detect putative biomarkers for PIBD compared to microbiome community composition sequence data alone.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Thyroid Organoids-Powerful Stem Cell-Derived Models in Basic and Translational Research.","authors":"Meghna Parakkal Shankar, Alessandra Boggian, Daniela Aparicio-Quiñonez, Sami Djerbib, Eduardo Rios-Morris, Sabine Costagliola, Mírian Romitti","doi":"10.3390/biom15050747","DOIUrl":"10.3390/biom15050747","url":null,"abstract":"<p><p>Thyroid organoids, three-dimensional in vitro models derived from stem cells, have emerged as a powerful tool for studying thyroid development, function, and disease mechanisms. These organoids recapitulate the key aspects of the thyroid gland, including the follicular structure, hormone production, and response to stimuli such as to the thyroid-stimulating hormone (TSH). Recent advances in thyroid organoid technology have established the basis for the modeling of development and thyroid diseases, including congenital hypothyroidism (CH), autoimmune conditions like Graves' disease and Hashimoto's thyroiditis, and other thyroid-related disorders. By utilizing pluripotent stem cells (PSCs) and adult tissue, researchers have generated organoid models suitable for dissecting the mechanisms associated with thyroid development while mimicking the genetic, functional, and inflammatory characteristics of thyroid diseases. Additionally, thyroid organoids offer the potential for personalized medicine by providing a platform to test therapies in a more clinically relevant context. This review highlights the recent progress in thyroid organoid generation, discusses their applications in dissecting the thyroid development mechanisms and disease modeling, and explores their potential for advancing our understanding of the thyroid physiology and pathology. Furthermore, we address the challenges and future directions in the optimization and use of thyroid organoids in translational research.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron Replacement Attenuates Hypoxic Pulmonary Hypertension by Remodeling Energy Metabolism via Regulating the HIF2α/Mitochondrial Complex I, III/ROS Axis.","authors":"Yumei Geng, Huijie Wang, Zhenzhong Bai, Rili Ge","doi":"10.3390/biom15050742","DOIUrl":"10.3390/biom15050742","url":null,"abstract":"<p><p>Iron deficiency is highly prevalent in patients with idiopathic pulmonary hypertension; nevertheless, its role and clinical significance in hypoxic pulmonary hypertension (HPH) remain elusive. Therefore, this study aims to clarify the role and molecular mechanisms of iron in HPH. By means of a retrospective analysis of clinical data from HPH patients and examinations of HPH animal models, we discovered that both HPH patients and animal models exhibit significant iron deficiency, characterized by reduced hepatic iron storage and elevated hepcidin expression. To further explore iron's role in HPH, we modulated iron metabolism through pharmacological and dietary interventions in chronic hypoxic animal models. The results showed that iron deficiency exacerbated chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy, while iron supplementation alleviated these conditions. Further investigations revealed that iron regulates HIF2α expression in pulmonary arterial endothelial cells (PAECs) under chronic hypoxia. Therefore, through in vivo and in vitro experiments, we demonstrated that HIF2α inhibition attenuates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Mechanistically, chronic hypoxia-mediated iron deficiency enhances HIF2α activation, subsequently suppressing iron/sulfur cluster assembly enzyme (ISCU) expression. This leads to decreased mitochondrial complexes I and III activity, increased reactive oxygen species (ROS) production, and inhibited oxidative phosphorylation. Consequently, metabolic reprogramming in PAECs results in a proliferation/apoptosis imbalance, ultimately exacerbating hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Collectively, our findings demonstrate that iron supplementation mitigates HPH progression by modulating HIF2α-mediated metabolic reprogramming in PAECs, revealing multiple therapeutic targets for HPH.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cathepsin B Levels Correlate with the Severity of Canine Myositis.","authors":"Valeria De Pasquale, Emanuela Vaccaro, Federica Rossin, Mariangela Ciampa, Melania Scarcella, Orlando Paciello, Simona Tafuri","doi":"10.3390/biom15050743","DOIUrl":"10.3390/biom15050743","url":null,"abstract":"<p><p>Cathepsins are protease enzymes vital for normal physiological functions, such as digestion, coagulation, hormone secretion, bone resorption, apoptosis, autophagy, and both innate and adaptive immunity. Their altered expression and/or activity is associated with various pathological conditions, including inflammatory processes. In this study, we investigated the expression levels of cathepsins in muscle specimens collected from dogs affected by inflammatory myopathy (IM) of variable severity established through histopathological analysis. Samples collected from dogs affected by IM at mild, moderate, and severe stages and from healthy (control) dogs were analyzed for the expression profile of 35 proteases using a proteome profiler array. Among the other proteases, cathepsin B was upregulated to an extent depending on disease progression. By exploring the molecular mechanisms underlying the impact of cathepsin B on the disease, we found that the upregulation of cathepsin B in diseased tissues correlates with increased TGFβ-1 expression levels and elevated phosphorylation levels of the TGFβ-1 signaling mediator SMAD2/3. These results suggest that cathepsin B might be involved in the onset and progression of fibrosis commonly occurring in IM diseased dogs. Overall, our findings reveal that modulating cathepsin B activity may hold therapeutic potential for IM.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal Plasticity-Dependent Paradigm and Young Plasma Treatment Prevent Synaptic and Motor Deficit in a Rett Syndrome Mouse Model.","authors":"Sofía Espinoza, Camila Navia, Rodrigo F Torres, Nuria Llontop, Verónica Valladares, Cristina Silva, Ariel Vivero, Exequiel Novoa-Padilla, Jessica Soto-Covasich, Jessica Mella, Ricardo Kouro, Sharin Valdivia, Marco Pérez-Bustamante, Patricia Ojeda-Provoste, Nancy Pineda, Sonja Buvinic, Dasfne Lee-Liu, Juan Pablo Henríquez, Bredford Kerr","doi":"10.3390/biom15050748","DOIUrl":"10.3390/biom15050748","url":null,"abstract":"<p><p>Classical Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the <i>MECP2</i> gene, resulting in a devastating phenotype associated with a lack of gene expression control. Mouse models lacking <i>Mecp2</i> expression with an RTT-like phenotype have been developed to advance therapeutic alternatives. Environmental enrichment (EE) attenuates RTT symptoms in patients and mouse models. However, the mechanisms underlying the effects of EE on RTT have not been fully elucidated. We housed male hemizygous <i>Mecp2</i>-null (<i>Mecp2^-/y</i>) and wild-type mice in specially conditioned cages to enhance sensory, cognitive, social, and motor stimulation. EE attenuated the progression of the RTT phenotype by preserving neuronal cytoarchitecture and neural plasticity markers. Furthermore, EE ameliorated defects in neuromuscular junction organization and restored the motor deficit of <i>Mecp2^-/y</i> mice. Treatment with plasma from young WT mice was used to assess whether the increased activity could modify plasma components, mimicking the benefits of EE in <i>Mecp2^-/y</i>. Plasma treatment attenuated the RTT phenotype by improving neurological markers, suggesting that peripheral signals of mice with normal motor function have the potential to reactivate dormant neurodevelopment in RTT mice. These findings demonstrate how EE and treatment with young plasma ameliorate RTT-like phenotype in mice, opening new therapeutical approaches for RTT patients.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Supplementation with Bioactive Compounds Improves Health and Rejuvenates Biological Age in Postmenopausal Women.","authors":"Estefanía Díaz-Del Cerro, Judith Félix, Mª Carmen Martínez-Poyato, Mónica De la Fuente","doi":"10.3390/biom15050739","DOIUrl":"10.3390/biom15050739","url":null,"abstract":"<p><p>Aging involves immune system deterioration (immunosenescence) and increased oxidative stress, both associated with morbidity and mortality. Menopause accelerates aging, highlighting the need for strategies to mitigate its effects in postmenopausal women. This study assessed the impact of daily oral supplementation for one month with 39 bioactive compounds (UNAMINA)-including amino acids, vitamins, and antioxidants-on immune function, redox parameters, stress-related hormones, and biological age in healthy postmenopausal women. Peripheral blood samples were collected before and after supplementation to analyze lymphocyte and neutrophil functions (adherence, chemotaxis, natural killer cell antitumor capacity, and lymphoproliferative response to mitogens), oxidative stress markers (antioxidant defenses such as glutathione peroxidase (GPx) and reductase activities, reduced glutathione (GSH) concentrations, as well as oxidants such as oxidized glutathione (GSSG), and lipid peroxidative damage) in blood cells, and stress-related hormones (dehydroepiandrosterone (DHEA) and cortisol) in plasma. Supplementation improved all immune cell functions and decreased oxidative stress (increasing antioxidants defenses such as GPx activity and GSH concentration and decreasing GSSG amount) and cortisol concentrations, whereas those of DHEA increased. The biological age also decreased. The results suggest that these bioactive compounds may be a beneficial strategy for promoting healthier aging in postmenopausal women by enhancing immune function, reducing biological age, improving redox balance, and regulating stress hormones.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LPS2336, a New TREK-1 Channel Activator Identified by High Throughput Screening.","authors":"Romane Boyer, Romane Bony, Maxence Maugis, Julien Schopp, Marion Leroux, Clément Michelin, Laurie Gonthier, Quentin Grzeskiewicz, Alexandre Jouannet, Youssef Aissouni, Bruno Didier, Mihaela Gulea, Nicolas Girard, Jean-Christophe Cintrat, Antoine Dumeige, Jérôme Busserolles, Sylvie Ducki, Stéphane Lolignier","doi":"10.3390/biom15050740","DOIUrl":"10.3390/biom15050740","url":null,"abstract":"<p><p>TWIK-related K+ (TREK-1) channels are involved in pain perception and their pharmacological activation has potential for pain relief. The development of new pharmacological tools to study these channels and enrich our knowledge of structure-activity relationships is therefore important. We optimized a high throughput screening method based on thallium flux monitoring for the detection of TREK-1 activators in chemical libraries. We screened 1040 compounds from the French National Essential Chemical Library and identified LPS2336 as a potent TREK-1 activator with an EC₅₀ of 11.76 µM. Thirty-three LPS2336 analogs were subsequently tested but none of them retained activity on TREK-1. In vivo, LPS2336 produces antinociceptive activity when administered systemically and, to a lesser extent, intracerebroventricularly, but not intrathecally, showing that targeting peripheral TREK-1 channels may be important to produce pain relief, with the interest of reducing potential central adverse effects. LPS2336 was shown to produce sedation and hypothermia with a narrow therapeutic window. As these adverse effects are also observed in TREK-1 knock-out mice, they are likely mediated by off-targets. Our work provides key optimization steps for thallium-based assays and a new pharmacological tool for the study of TREK-1 channels. It also raises the importance of investigating adverse effects in vivo at early stages of drug discovery.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Novel Imiqualine EAPB02303 Is a Potent Drug for Treating Acute Myeloid Leukemia.","authors":"Perla Makhoul, Rita Hleihel, Shaymaa Itani, Maguy Hamie, Stephanie Pagniagua-Gayraud, Cindy Patinote, Myriam Richaud, Raghida Abou Merhi, Marwan El-Sabban, Simon Galas, Carine Deleuze-Masquefa, Pierre-Antoine Bonnet, Hiba El Hajj","doi":"10.3390/biom15050741","DOIUrl":"10.3390/biom15050741","url":null,"abstract":"<p><p>Although 60% of AML patients respond well to standard chemotherapy, most patients eventually relapse, develop chemoresistance, and do not survive more than five years. Targeted therapies, including analogs of imiquimod belonging to the family of imiqualines, emerged as promising agents against AML. Notably, the first-generation imiqualine EAPB0503 proved selective potency against nucleophosmin-1-mutant (NPM1c) AML. Recently, chemical modifications of EAPB0503 led to the development of the lead compound from the second generation, EAPB02303. Here, we demonstrate that EAPB02303 displays 200-fold greater potency, broader activity across AML subtypes, and, importantly, a distinct mechanistic profile when compared to EAPB0503. Unlike EAPB0503, which primarily targeted <i>NPM1c</i> AML cells, EAPB02303 exhibits broad-spectrum activity across various AML subtypes. Remarkably, EAPB02303 anti-leukemic activity was attributed to the inhibition of PI3K/AKT/mTOR signaling activity. Nevertheless, NPM1c AML cells were more sensitive to EAPB02303, likely due to its ability to promote NPM1c protein degradation. In vivo, EAPB02303 potently reduced the leukemic burden and improved organ tumor infiltration in both wt-<i>NPM1</i> and <i>NPM1c</i> AML xenograft mice. Yet, the significant prolonged survival was exclusive to <i>NPM1c</i> AML xenografts, likely due to superior response conferred by NPM1c degradation. Overall, these findings highlight the potential of EAPB02303 as a powerful therapeutic agent for a range of AML subtypes, supporting its further development for broader clinical use.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12109066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144156676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}