Biomedicine & Pharmacotherapy最新文献

{"title":"Drug repurposing identifies proteasome inhibitors as antiproliferative agents counteracting inflammation-driven chemoresistance in triple-negative breast cancer organoids","authors":"Ariestya Indah Permata Sari ,&nbsp;Sittiruk Roytrakul ,&nbsp;Pamorn Chittavanich ,&nbsp;Duangporn Saengwimol ,&nbsp;Natanan Laosillapacharoen ,&nbsp;Jakkrit Khamjerm ,&nbsp;Suparerk Borwornpinyo ,&nbsp;Artit Jinawath ,&nbsp;Ronnarat Suvikapakornkul ,&nbsp;Panuwat Lertsithichai ,&nbsp;Prakasit Chirappapha ,&nbsp;Natini Jinawath ,&nbsp;Rossukon Kaewkhaw","doi":"10.1016/j.biopha.2025.118359","DOIUrl":"10.1016/j.biopha.2025.118359","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options, high relapse rates, and poor survival outcomes, largely due to chemoresistance. This study aimed to identify potential therapeutic strategies by repurposing FDA-approved anticancer drugs using patient-derived TNBC organoids from drug-resistant residual tumors post-chemotherapy. A high-throughput screen of 133 FDA-approved drugs, integrating image-based analysis and drug-sensitivity assays, identified the proteasome inhibitors bortezomib and carfilzomib as potent cytotoxic agents. Proteomic analysis, coupled with translation and cell cycle assays, showed that these inhibitors suppress TNBC organoid growth by downregulating ribosomal protein expression, leading to impaired translation and disrupted cell cycle progression. Furthermore, drug response dynamics confirmed their efficacy in overcoming clinical drug resistance. Transcriptomic profiling revealed that proteasome inhibitors counteract doxorubicin-induced, inflammation-driven resistance through dual anti-inflammatory and antiproliferative effects. Collectively, these findings support proteasome inhibition as a promising therapeutic strategy to overcome chemoresistance in TNBC.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118359"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of Bergamot Polyphenolic Fraction (BPF) in MASLD-Induced HFpEF: Mitigate diastolic dysfunction by targeting chronic low-grade inflammation","authors":"Cristina Carresi ,&nbsp;Antonio Cardamone ,&nbsp;Vincenzo Musolino ,&nbsp;Rocco Mollace ,&nbsp;Annamaria Tavernese ,&nbsp;Anna Rita Coppoletta ,&nbsp;Micaela Gliozzi ,&nbsp;Vincenzo Mollace","doi":"10.1016/j.biopha.2025.118375","DOIUrl":"10.1016/j.biopha.2025.118375","url":null,"abstract":"<div><h3>Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is an independent risk factor and a key contributor to the pathophysiology of heart failure with preserved ejection fraction (HFpEF), highlighting the urgent need for early detection and intervention. Bioimaging techniques provide valuable morphological and functional insights to monitor the disease progression and guide therapeutic strategies targeting early metabolic and inflammatory mechanisms that link these conditions. Alongside traditional pharmacological therapies, nutraceuticals are a promising candidate for primary prevention. Here, we investigated the potential role of BPF in mitigating MASLD-related HFpEF.</div></div><div><h3>Methods and results</h3><div>Male DIAMOND mice were randomly assigned to receive either a chow diet with tap water or a high-fat diet with sugar water. Starting at week 16, mice were further subdivided and treated with either vehicle or BPF (50 mg/kg/day po), until week 30. Echocardiographic analysis was conducted at the baseline and at week 30. Correlation and regression analyses were performed to assess the role of pro-inflammatory mediators in the onset of diastolic dysfunction. BPF supplementation ameliorated diastolic function, improving the E/A ratio, as well as left ventricular diastolic and systolic tissue strain dysfunction and dyssynchrony. These effects are induced by chronic low-grade inflammatory mediators straightly associated with the HFpEF phenotype.</div></div><div><h3>Conclusion</h3><div>Our results demonstrated that BPF improved diastolic dysfunction and reduced chronic low-grade inflammation. Since this inflammatory state is a key predisposing factor for the HFpEF, BPF supplementation emerged as a potential therapeutic strategy to alleviate early MASLD-related inflammation and pathological changes that contribute to the onset of cardiac dysfunction.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118375"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing SIRT1 activators for effective PCOS treatment: A new frontier","authors":"Shreyash Rajendra Moharir ,&nbsp;Mahesh Kumar Talamadla ,&nbsp;Puja Bhardwaj ,&nbsp;Arnab Banerjee ,&nbsp;Ruchi Jain Dey ,&nbsp;Kondapalli Venkata Gowri Chandra Sekhar","doi":"10.1016/j.biopha.2025.118361","DOIUrl":"10.1016/j.biopha.2025.118361","url":null,"abstract":"<div><div>Polycystic Ovarian Syndrome (PCOS) is the most prevalent hormonal disorder that affects metabolism, ovulation and menstrual cycles. SIRT1 belongs to the Sirtuin family, a group of NAD+ dependent class 3 histone deacetylases. This review explores the correlation between SIRT1 and PCOS and associated mechanisms of action like Insulin resistance, oxidative stress, inflammation and autophagy. Extensive studies have been done on SIRT1, how it was downregulated and contributed to conditions like insulin resistance. How activation of SIRT1 helps by deacetylating the different responsible transcriptional factors is discussed in the mechanisms briefly. Additionally, we discussed the molecular structures of the existing natural and synthetic SIRT1 activators and their roles, which were previously reported, from the chemistry perspective. This review gives insights into the challenges and advantages of SIRT1, which can be a beneficial therapeutic target for PCOS.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118361"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biochanin A as a potential agent in the disease therapy via mitochondria-mediated mechanisms","authors":"Meng-ai Miao ,&nbsp;Xiao-qi Wu ,&nbsp;Yuan Yuan ,&nbsp;Ya-jun Wang ,&nbsp;Wen-ting Dai","doi":"10.1016/j.biopha.2025.118363","DOIUrl":"10.1016/j.biopha.2025.118363","url":null,"abstract":"<div><div>Biochanin A (BCA), a naturally occurring phytoestrogen, derived from plants such as <em>Trifolium pratense L.</em> (red clover), has attracted considerable interest due to its diverse pharmacological properties. As a dietary supplement, BCA is commonly utilized to alleviate symptoms associated with estrogen deficiency. Beyond its estrogenic effects, accumulating evidence highlights its broad-spectrum bioactivities, including anti-cancer, anti-diabetes, neuroprotection, anti-inflammation, antioxidant, organ protection, etc. Mitochondrial dysfunction is increasingly recognized as a central pathological mechanism underlying numerous diseases, making it a pivotal therapeutic target. Despite extensive research on BCA’s pharmacological effects, a comprehensive review of its mitochondria-mediated mechanisms remains lacking. Here, on the basis of sufficient and comprehensive literature screening, we systematically review the extraordinary therapeutic potential of BCA in both <em>in vitro</em> and <em>in vivo</em> through its modulation of mitochondria-mediated pathways, including mitochondria-dependent apoptosis, reactive oxygen species (ROS) homeostasis, mitochondrial dynamics (fusion/fission), bioenergetics and mitochondrial biogenesis, as well as mitophagy. With this specific mechanism perspective, it helps us better understand the important role of mitochondria in the development of diseases and better target mitochondria to develop therapeutic regimens. Emerging studies highlight BCA’s significant efficacy in mitigating disease progression, positioning it as a promising candidate for clinical translation and future drug development.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118363"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eriocitrin and its derivatives against Alzheimer’s disease: Cumulative accounts of in vitro and in vivo studies","authors":"Kritika ,&nbsp;Sanjay ,&nbsp;Hae-Jeung Lee","doi":"10.1016/j.biopha.2025.118362","DOIUrl":"10.1016/j.biopha.2025.118362","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease (ND), and its adversities are not limited to the brain. Due to complex and interconnected pathologies with other NDs, an effective treatment for multidimensional AD-related adversities has yet to be reported. Several phytoconstituents have been reported and are currently being studied for their bioactive potential in AD. Eriocitrin, a dihydroflavonoid compound present in citrus fruits, such as lemons, limes, lemon peels, grapefruit, and vegetables, and processed items, such as beverages and wine, along with its derivatives hesperetin, hesperidin, eriodictyol, and homoeriodictyol, has been reported to possess various neuroprotective bioactivities, including anti-inflammatory, anti-oxidative, anti-amyloidogenic, anti-tau phosphorylation, and anti-apoptotic properties, in several <em>in vitro</em> and <em>in vivo</em> models. However, a comprehensive review summarizing and correlating the multidimensional bioactive potentials of eriocitrin and its derivatives against AD has yet to be compiled. This review extensively discusses the in-depth role of eriocitrin and its derivatives in ameliorating different AD-related signaling pathways both <em>in vitro</em> and <em>in vivo</em>, and summarizes the incorporation of eriocitrin like different plant-based flavonoids in long-term dietary practice to combat AD and other similar NDs. Additionally, this review suggests examining various nano-formulations of eriocitrin and its derivatives for their anti-AD effects in comparison to the parent compound. Furthermore, in-depth <em>in vitro</em> and <em>in vivo</em> studies, along with different clinical trials, should be conducted to fully elucidate the true potential of eriocitrin and its derivatives in AD pathology.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118362"},"PeriodicalIF":6.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Riboceine and N-acetylcysteine protect normal prostate cells from chemotherapy-induced oxidative stress while selectively modulating the cytotoxicity of methotrexate and docetaxel in prostate (PC-3) and breast cancer (MCF-7) cells","authors":"Trudy J. Philips ,&nbsp;Benoit Banga N’guessan ,&nbsp;Eunice Dotse ,&nbsp;Joseph Kofi Abankwah ,&nbsp;Regina Appiah-Opong","doi":"10.1016/j.biopha.2025.118355","DOIUrl":"10.1016/j.biopha.2025.118355","url":null,"abstract":"<div><h3>Background</h3><div>Cancer chemotherapy often results in severe side effects due to its non-selective cytotoxicity toward rapidly dividing normal cells. These adverse effects are largely driven by oxidative stress resulting from elevated reactive oxygen species (ROS) production. Riboceine (RIB), a synthetic precursor of glutathione (GSH), and N-acetylcysteine (NAC), a clinically used antioxidant, hold promise in mitigating oxidative damage; however, their impact on chemotherapy efficacy and the molecular mechanisms involved remain incompletely understood.</div></div><div><h3>Aim</h3><div>This study aimed to evaluate the cytoprotective potential of RIB and NAC against methotrexate (MET)- and docetaxel (DOC)-induced toxicity in normal and cancer cells, and to explore mechanistic pathways using integrative network pharmacology and molecular docking approaches.</div></div><div><h3>Methodology</h3><div>Cytotoxic effects of MET and DOC, alone or in combination with RIB or NAC, were assessed in normal prostate epithelial (PNT-2), prostate cancer (PC3), and breast cancer (MCF-7) cell lines using the Resazurin assay. Intracellular ROS and GSH levels were quantified using DCF and OPA fluorescence assays, respectively. Network pharmacology, protein–protein interaction (PPI) analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and molecular docking were conducted using SwissTargetPrediction, STRING, ShinyGO, Cytoscape, and AutoDock Vina platforms.</div></div><div><h3>Results</h3><div>MET and DOC showed dose-dependent cytotoxicity in PNT-2 and PC3 cells, but limited efficacy in chemoresistant MCF-7 cells. RIB and NAC significantly reduced ROS and restored GSH levels in PNT-2 cells, protecting them against oxidative injury. These antioxidants preserved anticancer effects in PC3 cells but reduced chemotherapy efficacy in MCF-7 cells, likely due to elevated redox buffering and transporter expression. Network analyses identified BCL-2, MAPK8, and SOD among key antioxidant and apoptotic targets. However, no direct experimental validation of these mechanisms was performed, and apoptotic markers such as Annexin V or caspase-3 were not assessed.</div></div><div><h3>Conclusion</h3><div>RIB and NAC provide selective cytoprotection to normal prostate cells during chemotherapy while maintaining anticancer effects in sensitive prostate cancer cells. However, their concurrent use in resistant cancers like MCF-7 may reduce drug efficacy, warranting cautious clinical application. Time-shifted antioxidant administration (e.g., post-chemotherapy) could be explored as a strategy to balance protection and efficacy. Future studies should include <em>in vivo</em> validation, apoptosis profiling, and protein-level mechanistic assays to confirm the predicted pathways.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118355"},"PeriodicalIF":6.9,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing the potential of CAR-NK cell therapy in gastrointestinal cancers: From bench to bedside","authors":"Ahmad Ghorbani Vanan ,&nbsp;Mohammad Reza Askari ,&nbsp;Kamyar Bagheri ,&nbsp;Mohammad Reza Arghand ,&nbsp;Farid Ghorbaninezhad ,&nbsp;Safa Tahmasebi ,&nbsp;Milad Taghizadeh-Anvar ,&nbsp;Samaneh Nouri ,&nbsp;Elham Safarzadeh","doi":"10.1016/j.biopha.2025.118380","DOIUrl":"10.1016/j.biopha.2025.118380","url":null,"abstract":"<div><div>Cancer is one of the leading causes of mortality worldwide, with gastrointestinal (GI) malignancies being among the most prevalent and lethal types. Traditional treatments for GI cancers, such as chemotherapy and radiotherapy, often result in severe side effects due to their lack of specificity. Among the various therapeutic strategies, immunotherapy has emerged as a promising and highly specific approach for treating GI cancers. Immunotherapeutic methods include the use of monoclonal antibodies with diverse specificities, as well as cell-based therapies. Engineered cell therapies, particularly those utilizing chimeric antigen receptor (CAR) T cells and natural killer (NK) cells, represent a forefront in innovative cancer treatment. While CAR-T cells have shown promise, CAR-NK cells offer distinct advantages, such as the ability to kill tumor cells independently of CAR signaling and their suitability for safe allogeneic transplantation.Given these benefits, CAR-NK cells have gained attention as either a complementary or alternative strategy to CAR-T cell therapy in GI cancers. Despite this potential, a comprehensive review specifically focused on CAR-NK therapy in GI malignancies has been lacking. The present study aims to address this gap by exploring the application of CAR-NK therapy in various GI cancers, including colorectal, pancreatic, hepatocellular, esophageal, gastric, and tongue cancers, highlighting the targeted tumor antigens and recent advancements in the field.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118380"},"PeriodicalIF":6.9,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein post-translational modifications: Novel molecular switches and strategies for targeted therapy in ischemic heart disease","authors":"Yuanyuan Chen ,&nbsp;Gaojie Xin ,&nbsp;Xiaoshan Cui ,&nbsp;Jiaming Gao ,&nbsp;Huiyu Zhang ,&nbsp;Fan Guo ,&nbsp;Zixin Liu ,&nbsp;Shujuan Xu ,&nbsp;Ce Cao ,&nbsp;Lanlan Li ,&nbsp;Hao Guo ,&nbsp;Jianhua Fu","doi":"10.1016/j.biopha.2025.118357","DOIUrl":"10.1016/j.biopha.2025.118357","url":null,"abstract":"<div><div>Protein post-translational modifications (PTMs), serving as crucial molecular switches regulating protein function and signaling pathways, have emerged as a research hotspot for elucidating the pathogenesis of Ischemic heart disease (IHD) and devising targeted therapeutic approaches. This review provides a comprehensive overview of the principal PTM types associated with IHD, encompassing phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, lactylation and succinylation. It also delves into the molecular mechanisms and key targets of PTMs in IHD pathology, primarily involving myocardial energy metabolism, calcium homeostasis, inflammatory responses, cell death, and myocardial fibrosis. Additionally, this paper evaluates the prospective applications of specific kinase modulators, PTM-targeting modifiers, and gene editing technologies in the treatment of IHD, and proposes a “modificatomics”-oriented precision intervention strategy, which offers a novel perspective for the management of IHD.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118357"},"PeriodicalIF":6.9,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of KMH-45, a novel MRGPRX2 inhibitor with enhanced anti-pruritic properties","authors":"Babina Sanjel ,&nbsp;Mahesh kumar Teli ,&nbsp;Surendra Kumar ,&nbsp;Ji-Hoon Oh ,&nbsp;Han-Joo Maeng ,&nbsp;Won-Sik Shim ,&nbsp;Mi-hyun Kim","doi":"10.1016/j.biopha.2025.118371","DOIUrl":"10.1016/j.biopha.2025.118371","url":null,"abstract":"<div><div>Pruritus, or itch, is a common complaint in dermatology, adversely affecting patient’s well-being and becoming unbearable when severe. Histamine induces itch by binding to the histamine receptor and antihistamines alleviate itch symptoms by blocking this action in many cases. However, the insufficient relief provided by antihistamines in various chronic conditions necessitates the development of anti-pruritic agents beyond the histamine mechanisms. In this study, we screened our in-house compounds with anti-inflammatory properties to assess their therapeutic potential in pruritus. In particular, protein-ligand interaction pattern of MRGPRX2 was investigated for the screening and KMH-45 was identified as a non-peptide inhibitor through molecular simulations of MRGPRX2 rotamer models, followed by calcium flux assay. Molecular mechanism study for pruritus targets revealed anti-pruritic efficacy of KMH-45 along with the regulation of anti-pruritic targets histamine receptor 1 and TRPA1 ion channel as well as MRGPR family. Moreover, KMH-45 dose-dependently inhibited peritoneal mast cell degranulation and demonstrated <em>in vivo</em> efficacy in the scratching behavior test. For further progression and application to clinical studies, the developability of KMH-45 and feature analysis of the MRGPRX2-ligand interaction pattern using GPCR-IPL Score was addressed.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118371"},"PeriodicalIF":6.9,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-associated changes in type I collagen promote the invasion of BRAFV600E mutated melanoma cells and their resistance to targeted therapies within three-dimensional matrix models","authors":"Laetitia Florent ,&nbsp;Charles Saby ,&nbsp;Marie-Pierre Courageot ,&nbsp;Christine Terryn ,&nbsp;Laurence Van Gulick ,&nbsp;Jade Vanmansart ,&nbsp;Florian Slimano ,&nbsp;Hamid Morjani","doi":"10.1016/j.biopha.2025.118351","DOIUrl":"10.1016/j.biopha.2025.118351","url":null,"abstract":"<div><div>Melanoma represents the most aggressive form of skin cancer, with the highest rate of mortality. Anti-mutated BRAF^V600E therapies, such as vemurafenib, has improved the prognosis for melanoma patients; however, resistance to these targeted therapies frequently emerges. Type I collagen—a key element of the tumor microenvironment—contributes to tumor progression and therapeutic resistance. With aging, type I collagen undergoes structural remodeling that alters its fibrillar organization and mechanical properties. Although these changes have been documented, their impact on BRAF^V600E-mutated melanoma cell behavior and drug response remains unclear. In this study, we utilized both <em>in vitro</em> and <em>in vivo</em> models to fill this critical gap by investigating how collagen remodeling associated with advanced age modulates BRAF^V600E-mutated melanoma response to vemurafenib. Our findings indicate that <em>in vitro</em>—using a 3D culture matrix model—old collagen promotes increased proliferation of 1205Lu cells and protects both 1205Lu and SKMEL28 cells from vemurafenib effects. This was associated with elevated YAP expression, suggesting a role for mechanotransduction in drug resistance. The 3D collagen matrix spheroid model revealed that aged collagen enhances the invasive properties of 1205Lu cells, which correlated with an upregulation of the AXL receptor. <em>In vivo</em>, vemurafenib reduced tumor growth in athymic mice xenografted with melanoma cells embedded in young collagen matrices, but not in those with aged collagen. Collectively, our data suggest that age-related alterations in type I collagen contribute to reduced efficacy of anti-BRAF^V600E therapies in BRAF^V600E-mutated melanoma.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"190 ","pages":"Article 118351"},"PeriodicalIF":6.9,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}