Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia","authors":"Gustavo Nery de Queiroz ,&nbsp;Keli Lima ,&nbsp;Marcella Cipelli ,&nbsp;Victoria Tomaz ,&nbsp;Luiz Gustavo Ferreira Cortez ,&nbsp;Marina de Franca Basto Silva ,&nbsp;Rafael Lucas Muniz Guedes ,&nbsp;Paulo Vidal Campregher ,&nbsp;Eduardo Magalhães Rego ,&nbsp;Niels Olsen Saraiva Câmara ,&nbsp;Leticia Veras Costa-Lotufo ,&nbsp;João Agostinho Machado-Neto","doi":"10.1016/j.bbadis.2025.168065","DOIUrl":"10.1016/j.bbadis.2025.168065","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) often develops resistance to the BCL2 inhibitor venetoclax through metabolic reprogramming. This study established acquired venetoclax-resistant AML models (MV4-11VR and MOLM-13VR) to explore resistance mechanisms and therapeutic strategies. Cell viability and apoptosis assays revealed robust acquired resistance to venetoclax upon intermittent drug exposure. Metabolic profiling revealed distinct adaptations: MV4-11VR cells favored glycolysis, while MOLM-13VR cells increased oxidative phosphorylation. Proteomic analysis supported these findings, showing pathway enrichment for carbohydrate metabolism in MV4-11VR and aerobic energy production in MOLM-13VR. Despite these differences, both models shared hyperactivation of the PI3K/AKT/mTOR pathway, as shown by RPS6 hyperphosphorylation. Apoptotic regulation also diverged between the cellular models in relation to modulated BCL2-related genes and activation of the MAPK signaling pathway. Targeting these metabolic changes with metformin (a mitochondrial complex I inhibitor) or KPT-9274 (a NAMPT inhibitor) re-sensitized resistant cells to venetoclax. Combination treatments showed strong synergy and near-complete cell elimination. These results highlight metabolic reprogramming as a heterogeneous but targetable resistance mechanism and support combining metabolic inhibitors with BCL2 blockade to treat refractory AML.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168065"},"PeriodicalIF":4.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tom70 prevents fibrotic activation of aortic valve interstitial cells via EPA-activated Autophagic flux","authors":"Ruochen Shao ,&nbsp;Junli Li ,&nbsp;Fengming Wu ,&nbsp;Wei Meng ,&nbsp;Changming Li ,&nbsp;Fangyang Huang ,&nbsp;Tianyi Qu ,&nbsp;Hao Zhou ,&nbsp;Yanbiao Liao ,&nbsp;Mao Chen","doi":"10.1016/j.bbadis.2025.168063","DOIUrl":"10.1016/j.bbadis.2025.168063","url":null,"abstract":"<div><h3>Background</h3><div>Translocase of outer mitochondrial membrane 70 (Tom70) has been implicated in the development of various cardiovascular diseases. However, its role in aortic valve fibrosis, an important feature of calcific aortic valve disease (CAVD), remains unclear.</div></div><div><h3>Objective</h3><div>This study aims to explore the potential role of Tom70 in aortic valve fibrosis, with a view to providing new insights into the clinical management of CAVD.</div></div><div><h3>Methods</h3><div>Proteomics, metabolomics and enrichment analysis were used to screen for differential molecules and signaling pathways. Western Blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to detect the expression levels of Tom70 and autophagy-related proteins. Gain- and loss-of-function experiments of Tom70 were conducted both in vivo and vitro to investigate its role in aortic valve fibrosis. Immunofluorescence staining, Masson staining, etc. were used to evaluate fibrosis. Confocal microscopy and transmission electron microscope (TEM) were utilized to detect autophagic flux.</div></div><div><h3>Results</h3><div>The expression of Tom70 was significantly downregulated in fibrocalcific aortic valve tissues from patients and in aortic valve interstitial cells (AVICs) following TGF-β1 stimulation. In vivo experiments revealed that Tom70 knockout exacerbated aortic valve fibrosis in rat. Mechanistic studies in rat AVICs indicated that impaired autophagic flux accelerates fibrotic activation in AVICs, and Tom70 modulates fibrotic activation through the regulation of autophagic flux. In addition, we identified eicosapentaenoic acid (EPA) as a key regulator of autophagic flux influenced by Tom70.</div></div><div><h3>Conclusion</h3><div>Overall, our study unveils a novel role of Tom70 in aortic valve fibrosis and elucidates its regulatory relationship with autophagic flux, providing new insights into the molecular mechanisms underlying CAVD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168063"},"PeriodicalIF":4.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The aging interactome: From cellular dysregulation to therapeutic frontiers in age-related diseases","authors":"Louay Abo Qoura ,&nbsp;Alexey V. Churov ,&nbsp;Olga N. Maltseva ,&nbsp;Mikhail S. Arbatskiy ,&nbsp;Olga N. Tkacheva","doi":"10.1016/j.bbadis.2025.168060","DOIUrl":"10.1016/j.bbadis.2025.168060","url":null,"abstract":"<div><div>Biological aging is a complex, multifaceted process characterized by the progressive erosion of cellular homeostasis, driven by intersecting pathways of inflammaging, immune senescence, mitochondrial dysfunction, and genomic instability. This review delineates current knowledge on the interconnected mechanisms underlying aging-related diseases, including atherosclerosis, obesity, sarcopenia, neurodegenerative disorders, rheumatoid arthritis, and cancer. We further discuss the critical role of contributing factors such as microbiome dysbiosis, sex differences, and exosome-mediated communication in modulating disease progression. Advancements in multi-omics technologies and AI-driven biomarkers, particularly epigenetic clocks, are highlighted for their ability to precisely quantify biological aging and stratify disease risk. Finally, we explore the therapeutic potential and promising clinical trials of targeting these shared mechanisms with senolytics, mitochondrial enhancers, and immunomodulators, offering a paradigm shift from disease-specific treatment to holistic interventions designed to extend healthspan.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168060"},"PeriodicalIF":4.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is tau pathology a relevant factor in neuronal damage induced by alcohol and other drugs?","authors":"Margrethe A. Olesen ,&nbsp;Andrés Ancía ,&nbsp;Rodrigo A. Quintanilla","doi":"10.1016/j.bbadis.2025.168059","DOIUrl":"10.1016/j.bbadis.2025.168059","url":null,"abstract":"<div><div>Unrestricted alcohol consumption and other substances like methamphetamine (ecstasy), opioids, cannabis, and cocaine have generated serious health concerns in the world population. The abusive use of these substances produces neuropathological alterations that could lead to cognitive decline and neurodegeneration. Pathological damage generated by these drugs resembles neurodegenerative changes observed in neurological disorders (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and others. One of the relevant elements distinguished in these diseases is the aggregation of intraneuronal proteins and deregulation of the neuronal cytoskeleton. In this context, the toxic modification of tau protein, a microtubule-associated protein (MAP), has raised new interest in drug and alcohol abuse research. Tau can undergo different pathological changes in which its anomalous phosphorylation and truncation state are relevant for NDs. These modifications produce a detachment from microtubule structures, affecting axonal transport and synaptic plasticity.</div><div>Current studies suggest that alcohol and drug abuse may affect the mechanisms behind tau phosphorylation, inducing dysregulation of kinase/phosphatase activities and toxic tau accumulation. These alterations could be a key element that contributes to cognitive decline and neurodegeneration caused by substance abuse.</div><div>Therefore, it is pivotal to understand how alcohol and other drugs contribute to neuronal damage by inducing tau pathology. This knowledge could generate new strategies and biomedical targets to reduce addictive consumption, neurodegeneration, and cognitive decline produced by substance abuse.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168059"},"PeriodicalIF":4.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin protects against PIICS-induced liver injury by suppressing iron-induced lipid peroxidation: Insights from network pharmacology and experimental validation","authors":"Jiawen Chen ,&nbsp;Jiali Liu ,&nbsp;Gang Wang ,&nbsp;Xinran Liang ,&nbsp;Yuanbo Xue ,&nbsp;Ming Chen ,&nbsp;Xiancheng Chen ,&nbsp;Jianfeng Duan ,&nbsp;Wenkui Yu","doi":"10.1016/j.bbadis.2025.168053","DOIUrl":"10.1016/j.bbadis.2025.168053","url":null,"abstract":"<div><h3>Background</h3><div>Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) drives severe metabolic dysregulation and hepatic injury, characterized by hepatocyte damage and fibrosis. While curcumin (CUR) exhibits hepatoprotective properties, its role in PIICS-induced liver injury remains unexplored.</div></div><div><h3>Methods</h3><div>This study investigates the efficacy and mechanisms of CUR against PIICS-induced hepatic damage. Murine PIICS models underwent hepatic histopathology (H&amp;E staining, TEM), RNA sequencing, and targeted metabolomics to identify injury markers. CUR's effects were assessed via biochemical, transcriptomic, and metabolomic analyses. Network pharmacology, molecular docking, and qPCR were employed to validate CUR targets.</div></div><div><h3>Results</h3><div>PIICS mice exhibited elevated serum ALT, AST, IL-6, and TNF-α levels, alongside histopathological evidence of inflammatory infiltration. Transcriptomics revealed dysregulation in lipid metabolism, redox homeostasis, and iron-binding pathways. Metabolomics identified hepatic polyunsaturated fatty acid (PUFA) depletion, increased ferrous ions, lipid peroxidation (4-HNE, MDA), and reduced antioxidants (GSH, SOD). CUR treatment alleviated liver injury, restored redox balance, and suppressed ferroptosis markers. Integrated analyses demonstrated that CUR targets ferroptosis-related pathways, modulating lipid metabolism, iron homeostasis, and oxidative stress.</div></div><div><h3>Conclusion</h3><div>CUR mitigates PIICS-induced liver injury by counteracting ferroptosis through modulation of lipid metabolism, iron homeostasis, and oxidative stress, offering a promising therapeutic strategy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168053"},"PeriodicalIF":4.2,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling","authors":"Yining Feng ,&nbsp;Fei Chen ,&nbsp;Chenglong Mu ,&nbsp;Luqi Wang ,&nbsp;Yuhan Jiang ,&nbsp;Dan Liu ,&nbsp;Dameng Li ,&nbsp;Chen Liang ,&nbsp;Yanhua Zhai ,&nbsp;Tao Yang ,&nbsp;Alan Wells ,&nbsp;Amanda M. Clark ,&nbsp;Liang Wei ,&nbsp;Bo Ma","doi":"10.1016/j.bbadis.2025.168056","DOIUrl":"10.1016/j.bbadis.2025.168056","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, playing a key role in breast cancer (BrCa) progression and chemotherapy response. While TAMs exhibit diverse phenotypes, the M1/M2 classification remains widely used. M1-like macrophages are known for tumor-killing properties, whereas M2-like macrophages promote tumor growth. However, the impact of TAM subtypes on chemotherapy response remains inconsistent. In this study, we found that M1-like macrophages or their conditioned medium (CM) induced greater BrCa cell death and inhibited proliferation compared to M2-like macrophages. Surprisingly, BrCa cells surviving M1-like macrophage-induced killing displayed increased chemotherapy resistance, independent of proliferation. Transcriptomic profiling indicated upregulation of the JAK–STAT signaling pathway, with elevated STAT3 phosphorylation subsequently confirmed at the protein level. Inhibition of JAKs with Ruxolitinib reduced STAT3 activation and restored chemotherapy sensitivity. Our findings highlight the dual role of M1-like macrophages, demonstrating both tumoricidal activity and the potential to induce chemotherapy resistance in surviving tumor cells, offering insights for macrophage-targeted therapies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168056"},"PeriodicalIF":4.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles of heme oxygenase 2 (HO-2) in cancer: Implications for diagnosis and therapy","authors":"Sonny C. Ramos ,&nbsp;Seung-Hyun Jeong ,&nbsp;Yong-An Lee ,&nbsp;Jong-Jin Kim","doi":"10.1016/j.bbadis.2025.168057","DOIUrl":"10.1016/j.bbadis.2025.168057","url":null,"abstract":"<div><div>Heme oxygenases (HOs) are critical enzymes that regulate cellular redox balance, immune signaling, and iron metabolism through the degradation of heme into biliverdin, carbon monoxide (CO), and ferrous iron (Fe²⁺). While HO-1, the inducible isoform, has been extensively studied for its roles in tumor progression, inflammation, and therapy resistance, HO-2, the constitutively expressed isoform, has historically received limited attention. However, emerging evidence suggests that HO-2 contributes to cancer pathogenesis through mechanisms distinct from HO-1, including the regulation of tumor-initiating cells, angiogenesis, oxidative stress responses, and immune modulation. These findings position HO-2 as an underexplored yet promising target for cancer diagnosis and therapy. In this review, we summarize the structural and functional differences between HO-1 and HO-2, examine the emerging roles of HO-2 in various malignancies, and discuss its potential as a diagnostic biomarker and therapeutic target. We also highlight recent advances in selective chemical tools that enable the visualization and functional inhibition of HO-2 in cancer models.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168057"},"PeriodicalIF":4.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From aging to space: A comparative biology of skeletal muscle degeneration","authors":"Rizwan Qaisar","doi":"10.1016/j.bbadis.2025.168058","DOIUrl":"10.1016/j.bbadis.2025.168058","url":null,"abstract":"<div><div>Sarcopenia, the progressive loss of skeletal muscle mass and function with age, represents a major clinical concern, particularly in the context of disuse and unloading conditions such as simulated microgravity. This review explores the molecular, cellular, and physiological responses of skeletal muscle to simulated microgravity and compares them with those observed during aging-associated sarcopenia. A central focus is placed on impaired excitation–contraction coupling, altered calcium homeostasis, and dysregulation of signalling pathways critical for muscle maintenance. Simulated microgravity induces rapid suppression of the IGF-1/Akt/mTOR axis, activation of FOXO-mediated proteolysis, and mitochondrial dysfunction via AMPK-PGC-1α inhibition, paralleling but accelerating the trajectory observed with aging. Unique to the effects of simulated microgrvity is the early upregulation and partial reversibility of myostatin-Smad signalling and autophagy activation, which diverge in pattern and timing from aging. Additionally, mechanotransduction pathways such as YAP/TAZ and redox-sensitive systems like NRF2 respond differently in simulated microgravity and sarcopenia. We further highlight the emerging role of neuromuscular junction (NMJ) instability, fiber-type switching, and nuclear calcium signalling in both contexts, emphasizing their contribution to excitation–transcription coupling and long-term muscle adaptation. The insights from simulated microgravity models not only deepen our mechanistic understanding of sarcopenia but also offer a controlled platform to explore interventions. By delineating the overlapping and distinct molecular signatures of disuse-induced and age-related muscle loss, this review provides a foundation for developing targeted countermeasures for muscle atrophy in both clinical and spaceflight settings.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168058"},"PeriodicalIF":4.2,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXO1-driven endothelial senescence in bicuspid aortic valve-associated thoracic aortic aneurysm","authors":"Miqi Zhou ,&nbsp;Minjie Hu ,&nbsp;Lu Ding ,&nbsp;Yuhao Chen ,&nbsp;Xiaoli Ren ,&nbsp;Runze Dong ,&nbsp;Peifeng Jin ,&nbsp;Congkuo Du ,&nbsp;XueJiao Chen ,&nbsp;Xiaofang Fan ,&nbsp;Xiufang Chen ,&nbsp;Ming Li ,&nbsp;Yongsheng Gong ,&nbsp;Yongyu Wang","doi":"10.1016/j.bbadis.2025.168052","DOIUrl":"10.1016/j.bbadis.2025.168052","url":null,"abstract":"<div><div>Bicuspid aortic valve (BAV) is a congenital malformation that predisposes individuals to thoracic aortic aneurysm (TAA), with endothelial dysfunction playing a pivotal role in its pathogenesis. Endothelial cell senescence is a hallmark of endothelial dysfunction, yet direct evidence linking endothelial senescence to BAV-TAA has not been established. In this study, we generated induced pluripotent stem cells (iPSCs) from both BAV-TAA patients and healthy controls, subsequently differentiating them into endothelial cells (iECs). Our findings revealed that BAV-TAA-iECs exhibited senescence phenotype, including impaired proliferation, diminished migratory capacity, upregulated senescence markers (p53, p21, p16), and a pronounced senescence-associated secretory phenotype (SASP). Transcriptomic analysis through RNA sequencing indicated aberrant activation of the FOXO signaling pathway in BAV-TAA-iECs which might contribute to BAV-TAA-iEC senescence. Inhibition of FOXO1 signaling using AS1842856 effectively reversed the senescence phenotype, restored endothelial nitric oxide synthase (eNOS) expression, attenuated SASP cytokine levels, and mitigated inflammation through the p65 and p38 signaling pathways. These findings suggest that endothelial cell senescence plays a critical role in the pathogenesis of BAV-TAA, and targeting FOXO1 signaling may represent a promising therapeutic strategy for BAV-associated aortic diseases.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168052"},"PeriodicalIF":4.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of estrogen receptor alpha promotes distant metastasis through epithelial-mesenchymal transition in luminal-type breast cancer","authors":"Wen-Der Lin ,&nbsp;Yu-Chia Chen ,&nbsp;Forn-Chia Lin ,&nbsp;Jhih-Kai Pan ,&nbsp;Meng-Han Chen ,&nbsp;Hsiang-Ling Chen ,&nbsp;Wei-Pang Chung ,&nbsp;Hui-Chuan Cheng ,&nbsp;Michael Hsiao ,&nbsp;Chia-Ning Yang ,&nbsp;Pei-Jung Lu","doi":"10.1016/j.bbadis.2025.168055","DOIUrl":"10.1016/j.bbadis.2025.168055","url":null,"abstract":"<div><div>Breast cancer (BC) is a global health challenge, with approximately 75 % of cases classified as estrogen receptor alpha (ER-α)-positive luminal subtype. Although hormone therapies such as tamoxifen have improved outcomes, a subset of ER-α-positive BC patients develop resistance, resulting in early metastasis. Our research shows that ER-α loss is more frequent in distant metastases and is associated with poorer survival. We investigated the role of ER-α expression in BC progression, metastasis, and recurrence using comprehensive in vitro and in vivo models. Low ER-α expression in primary tumors was associated with increased metastasis and recurrence in ER-α-positive BC. Luminal BC cells with low ER-α expression exhibited increased invasiveness, whereas ER-α overexpression in triple-negative BC cells suppressed metastatic behavior. Mechanistically, ER-α downregulation promoted epithelial-mesenchymal transition (EMT) and upregulated MMP9 expression in BC cells. These findings suggest that ER-α loss facilitates BC metastasis through the EMT process. Relatively low ER-α expression may serve as a potential prognostic indicator in ER-positive luminal BC. These results have potential implications for predicting outcomes in ER-positive BC and highlight the importance of personalized treatment strategies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 1","pages":"Article 168055"},"PeriodicalIF":4.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}