Molecular medicine reports最新文献

{"title":"Integrin αVβ3 as a context‑dependent regulator of bone homeostasis: Insights into osteoporosis pathogenesis and therapeutic targeting (Review).","authors":"Changshun Chen, Xingxi Hu, Sixing Wei, Yongcheng Deng, Qinggang Zhao, Ge Chen, Zhong Cheng, Jianhua Ji, Jinyi Gu","doi":"10.3892/mmr.2026.14023","DOIUrl":"10.3892/mmr.2026.14023","url":null,"abstract":"<p><p>Osteoporosis (OP) is a multifactorial skeletal disorder characterized by progressive bone loss, microarchitectural deterioration and an increased risk of fragility fractures resulting from disrupted bone remodeling. Integrin αVβ3 functions as an important regulator of bone homeostasis by coordinating bone cell‑extracellular matrix interactions, mechanotransduction and intracellular signaling across multiple bone cell populations. Through context‑dependent actions in osteoclasts, osteoblasts, osteocytes, endothelial cells and immune cells, integrin αVβ3 influences osteoclast adhesion and bone resorption, osteoblast differentiation, angiogenesis, inflammatory responses, and estrogen‑associated skeletal remodeling. These diverse functions position integrin αVβ3 at the interface of the multiple signaling pathways involved in maintaining bone‑metabolic homeostasis. The present review summarizes current evidence regarding the molecular mechanisms underlying the integrin αVβ3‑mediated regulation of bone remodeling, discusses the cell‑specific and microenvironment‑dependent functions of integrin αVβ3 in OP pathogenesis, and critically evaluates the challenges and future directions for translating integrin αVβ3‑targeted strategies into clinical applications against OP.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMAL1 in cardiovascular diseases: Molecular mechanisms, circadian regulation and translational perspectives (Review).","authors":"Yu Liang, Tingjin Chen, Xuemei Wen, Dan Liu, Zhongjian Zhang, Weiqing Li, Hengdi Zhang","doi":"10.3892/mmr.2026.14032","DOIUrl":"10.3892/mmr.2026.14032","url":null,"abstract":"<p><p>Brain and muscle ARNT‑like 1 (BMAL1) is a core transcription factor of the molecular circadian clock and links daily timing with cardiovascular electrophysiology, metabolism, vascular function and inflammation. Altered BMAL1 expression or rhythmicity has been reported in arrhythmias, atherosclerosis, myocardial ischemia/reperfusion injury and heart failure. However, its specific role has remained elusive, as local effects in cardiovascular cells are often mixed with the broader effects of whole‑body circadian disruption. The present review addressed this gap by separating evidence from central and peripheral clocks, cell‑specific and systemic models, and experimental and human studies. Cardiomyocyte‑specific models provide relatively direct evidence that the local clock supports electrical stability, substrate use, mitochondrial homeostasis and contractile function. However, in endothelial cells, vascular smooth muscle cells and immune cells, the effects of BMAL1 are more variable and depend on cell type, metabolic conditions, disease stage and circadian phase. Human evidence remains mainly associative, whereas most mechanistic findings come from cell and animal studies. The present review also assessed small‑molecule clock modulators, chronotherapy and non‑pharmacological interventions, as well as time‑resolved multi‑omics and machine‑learning approaches. Current evidence does not support viewing BMAL1 as simply protective or harmful. A selective BMAL1‑binding small molecule has recently been identified, but its cardiovascular efficacy and safety have not been established. In addition, the clinical benefits of chronotherapy vary across treatments and patients. Further translation will require tissue‑specific human models, repeated sampling across biological time and prospective studies of treatment guided by individual circadian phases.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep deprivation exacerbates lens‑induced myopia in association with ERK/NF‑κB pathway activation.","authors":"Xueli Yang, Zhou Zhang, Chengbai Zhu, Jianbo Li, Wenting Gong, Ruirui Yang, Lipeng Guan","doi":"10.3892/mmr.2026.14029","DOIUrl":"10.3892/mmr.2026.14029","url":null,"abstract":"<p><p>The objective of the present study was to examine the molecular mechanisms by which sleep deprivation (SD) exacerbates lens‑induced myopia (LIM). Guinea pig models were established for the LIM and LIM + SD groups, with 15 animals per group. Guinea pigs in the LIM + SD group underwent 20 h of daily SD in addition to wearing concave lenses on the right eye. Additional guinea pig models were established for the LIM + SD and LIM + SD + BVD‑523 groups, each containing 15 animals. The LIM + SD + BVD‑523 group received oral administration of BVD‑523, an inhibitor of the ERK1/2. Biological parameters, including diopter and axial length, were measured. Retinal dopamine (DA) levels were evaluated with high‑performance liquid chromatography-electrochemistry, tyrosine hydroxylase (TH) expression by immunofluorescence staining, retinal ERK/NF‑κB signaling pathway expression by western blotting and retinal inflammatory cytokine levels by ELISA. Relative to the LIM group, the LIM + SD group demonstrated increased diopter and axial length, decreased retinal DA and TH levels, elevated inflammatory cytokine expression and activation of the ERK/NF‑κB signaling pathway, which were associated with myopia progression. However, administration of BVD‑523 inhibited increases in diopter and axial length, restored retinal DA and TH levels and downregulated inflammatory cytokine expression, which was associated with alleviation of myopia. In conclusion, SD may exacerbate LIM in association with ERK/NF‑κB pathway activation, representing a potential therapeutic target for myopia, as the ERK1/2 inhibitor BVD‑523 can suppress SD‑induced myopia.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the circadian rhythm in squamous cell carcinoma: From molecular mechanism to therapy (Review).","authors":"Mary-Lyn Eichhorn, Anna M Dmitrieva, Lydia Meder","doi":"10.3892/mmr.2026.14011","DOIUrl":"10.3892/mmr.2026.14011","url":null,"abstract":"<p><p>Squamous cell carcinoma (SCC) comprises a heterogeneous group of malignancies with distinct molecular characteristics, clinical behavior and therapeutic responses, highlighting the need for personalized treatment strategies. Circadian rhythms regulate fundamental physiological processes, including cell proliferation, metabolism, DNA repair and immune function, and emerging evidence suggests that circadian regulation may influence pathways relevant to SCC biology and treatment response. This review summarizes current knowledge on the role of circadian regulation in SCC, with particular emphasis on lung SCC, focusing on core clock genes, their interactions with oncogenic and immune‑related pathways, and their therapeutic implications. We discuss current evidence supporting chronotherapy as a potential component of personalized SCC treatment while addressing important limitations, including the predominance of preclinical studies, limited SCC‑specific clinical evidence and extrapolation from other tumor types. Finally, we outline key research priorities for translating circadian biology into clinical SCC management.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ameliorative effects of <i>Paulownia tomentosa</i> flower absolute on atopic dermatitis‑related responses in mast cells and keratinocytes and its chemical composition.","authors":"Da Yeon Yoo, Kyung Jong Won, Do Yoon Kim, Yoon Yi Kim, Ji Hye Bae, Ji Seong Yun, Hwan Myung Lee","doi":"10.3892/mmr.2026.14015","DOIUrl":"10.3892/mmr.2026.14015","url":null,"abstract":"<p><p><i>Paulownia tomentosa</i> (PT) exhibits diverse biological activities, including anti‑inflammatory and antioxidant effects; however, its potential effects on atopic dermatitis (AD) are unclear. The present study examined the effects of PT flower absolute (PTFAb) on AD‑related responses, particularly mast cell activation and keratinocyte barrier‑related responses. PTFAb was isolated from PT flowers using a solvent extraction method and its chemical composition was analyzed by gas chromatography/mass spectrometry, through which 13 components were identified. <i>In vitro</i> biological tests on rat basophilic leukemia cells (RBL‑2H3 cells; a commonly used mast cell model) and human epidermal keratinocytes (HaCaT cells) were performed using water‑soluble tetrazolium salt, 5‑bromo‑2'‑deoxyuridine incorporation, Boyden chamber, immunoblotting and enzyme‑linked immunosorbent assay methods. All experiments were conducted on cells at nontoxic PTFAb concentrations. PTFAb reduced the expression of the v‑soluble N‑ethylmaleimide‑sensitive factor attachment protein receptor proteins vesicle‑associated membrane protein (VAMP)7 and VAMP8 in RBL‑2H3 cells. In RBL‑2H3 cells stimulated with anti‑dinitrophenyl (DNP)‑immunoglobulin E and DNP‑bovine serum albumin, PTFAb suppressed the release of β‑hexosaminidase and histamine (indicators of mast cell degranulation), and the phosphorylation of spleen tyrosine kinase, phosphatidylinositol 3‑kinase and protein kinase B. PTFAb also induced proliferation, migration, and type Ⅰ and Ⅳ collagen synthesis. Furthermore, PTFAb upregulated tumor necrosis factor‑α (TNF‑α)‑reduced filaggrin expression and the expression of hyaluronan synthase (HAS)‑2 and HAS‑3 in HaCaT cells, and reduced TNF‑α‑increased intercellular adhesion molecule‑1 expression in HaCaT cells. In conclusion, PTFAb may exert inhibitory effects on mast cell degranulation‑related responses and potentiate skin barrier‑related responses, suggesting its potential to modulate AD‑related cellular responses or skin barrier function.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).","authors":"Shilong Meng, Xinlei Fu, Yawei Xu, Zhiliang Peng, Xu Zhang, Yanguang Cao, Binbin Tang, Xiaolin Shi, Kang Liu","doi":"10.3892/mmr.2026.14020","DOIUrl":"10.3892/mmr.2026.14020","url":null,"abstract":"<p><p>Mitochondria‑associated endoplasmic reticulum membranes (MAMs) are specialized endoplasmic reticulum (ER) membrane domains at ER‑mitochondrial contact sites that coordinate Ca²⁺ transfer, lipid exchange, mitochondrial quality control and cellular stress responses. In osteoporosis, intervertebral disc degeneration, osteoarthritis and sarcopenia/skeletal muscle atrophy, altered ER‑mitochondrial communication has been linked to recurrent disturbances in Ca²⁺ homeostasis, mitochondrial function, ER stress, inflammatory signaling and cell fate. However, evidence for MAM involvement varies markedly in directness and biological context. This narrative review compares these evidence patterns and their therapeutic implications across degenerative musculoskeletal disorders. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected osteoarthritis models; osteoporosis is supported mainly by studies of MAM‑associated regulators and functional pathways, whereas sarcopenia‑specific mechanisms remain largely informed by aging muscle and related experimental models. The direction and consequences of contact remodeling also vary with cell type, metabolic state and disease stage, arguing against a uniform gain‑ or loss‑of‑contact model. Interventions targeting contact‑site regulators or MAM‑related Ca²⁺ and mitochondrial pathways have shown preclinical benefit, but MAM‑specific target engagement and human validation remain limited. Progress will require paired structural and functional assessment together with validation in clinically characterized human tissues and patient‑derived systems.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effects of exosome‑based hyperin delivery in a cyclophosphamide‑induced mouse model of diminished ovarian reserve.","authors":"Yi Ying, Yue Wu, Ji Zhou, Yaming Wang, Hongtao Yin, Gang Lu, Ruolang Pan, Liangzhong Lv","doi":"10.3892/mmr.2026.14021","DOIUrl":"10.3892/mmr.2026.14021","url":null,"abstract":"<p><p>The development of more effective and affordable strategies for the treatment of diminished ovarian reserve (DOR) is of notable importance due to its increasing prevalence in young patients and the limited efficacy of current clinical interventions in restoring fertility. The present study investigated the efficacy of umbilical cord‑derived mesenchymal stem cell (UCMSC)‑derived exosome‑based hyperin delivery in ameliorating cyclophosphamide (CP)‑induced DOR in mice, and elucidated the potential underlying mechanisms of resulting therapeutic benefits. Exosomes were isolated from UCMSCs and encapsulated with hyperin using ultrasonication. The DOR mouse model itself was established via treatment with CP; these model mice were then treated with hyperin, UCMSC‑exosome controls or hyperin‑encapsulated UCMSC‑exosomes. After treatment, body weight, estrous cycles and general health were monitored. Ovarian tissues were evaluated histologically, and serum levels of anti‑Müllerian hormone, follicle‑stimulating hormone and estradiol were measured via enzyme‑linked immunosorbent assay. Ovarian expression of the autophagy markers LC3 II, Beclin‑1 and P62 was analyzed via western blotting. CP treatment led to a notable deterioration in general health, body weight and ovarian function, as evidenced by altered estrous cycles and reduced follicle counts. Treatment with hyperin‑loaded UCMSC‑exosomes resulted in improvements in body weight, the restoration of estrous cycles. Notably, compared with the model group, mice treated with hyperin‑loaded UCMSC‑exosomes demonstrated increased primordial follicle counts and decreased atretic follicle counts. Treatment with hyperin‑loaded UCMSC‑exosomes modulated autophagic activity within the ovaries, with reduced LC3‑Ⅱ and beclin‑1 levels and increased P62 levels following treatment with hyperin‑loaded UCMSC‑derived exosomes. UCMSC‑derived exosomes loaded with hyperin effectively mitigated the adverse effects of CP on ovarian function, potentially via the modulation of autophagic processes. These findings supported the therapeutic potential of engineered exosomes for treating DOR, highlighting a novel approach for fertility preservation and reproductive medicine.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in biomarkers of benzene exposure and toxicity: From mechanistic insights to occupational health applications (Review).","authors":"Yuanshe Huang, Zhenjun Xi, Jingxin Mao, Xiaobing Li","doi":"10.3892/mmr.2026.14028","DOIUrl":"10.3892/mmr.2026.14028","url":null,"abstract":"<p><p>Benzene is a toxic aromatic hydrocarbon widely used in industrial production, posing a notable occupational health threat. Classified as a Group 1 carcinogen, chronic benzene exposure primarily targets the hematopoietic system, causing leukopenia, thrombocytopenia, aplastic anemia and acute myeloid leukemia. Furthermore, emerging evidence highlights its multi‑systemic toxicity, inducing oxidative stress, DNA damage and cellular dysfunction, across the nervous, respiratory, dermatological, reproductive, immune and cardiovascular systems. The present review systematically summarizes recent advances in these occupational hazards and the evolving landscape of benzene biomonitoring. Traditional exposure biomarkers, such as urinary phenol and hydroquinone, are increasingly being supplemented by highly specific metabolites, notably S‑phenylmercapturic acid, for low‑dose exposure assessments. Effect biomarkers capture early biological damage through hematological indices and molecular alterations, while susceptibility biomarkers, such as cytochrome P450 2E1, glutathione S‑transferase mu 1 and DNA repair gene polymorphisms, identify genetically vulnerable populations. Additionally, emerging non‑invasive tools, particularly exhaled breath metabolomics, show promise in correlating specific metabolites with hematopoietic function. By integrating mechanistic insights into multi‑organ toxicity with advanced multi‑omics profiling, the present review highlights a critical paradigm shift from reactive traditional monitoring to artificial intelligence‑driven, multi-biomarker integration frameworks. Ultimately, it provides a forward-looking roadmap for individualized risk stratification and precision occupational health surveillance in the low‑dose exposure era.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactylation in gastric cancer: From mechanisms to clinical applications (Review).","authors":"Yuliang Fang, Peng Chen, Yuhong Gao, Yanpiao Li, Xue Li","doi":"10.3892/mmr.2026.14030","DOIUrl":"10.3892/mmr.2026.14030","url":null,"abstract":"<p><p>Gastric cancer (GC) is one of the most common malignant tumors worldwide. Metabolic reprogramming and epigenetic dysregulation represent its key pathological characteristics. As a novel lactate‑mediated post‑translational modification, lactylation converts metabolic signals into epigenetic and protein functional regulation, and it is extensively and aberrantly activated in GC. Lactylation drives the malignant progression of GC by promoting cell proliferation, invasion, metastasis and stemness. In addition, lactylation suppresses antitumor immune cell functions, and mediates immune escape and therapeutic resistance. Clinically, global lactylation levels and specific lactylation sites can serve as independent prognostic biomarkers, and corresponding risk models enable prognostic stratification and prediction of immunotherapy response. Intervention strategies targeting lactate production, lactyltransferases and downstream effector axes have emerged as promising directions for GC treatment. The present review summarizes the regulatory mechanisms, biological functions and clinical translational value of lactylation in GC, aiming to provide novel insights for precision diagnostics and therapeutics.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A four‑gene signature identifies TKI‑induced persister cells and uncovers a ZLN005‑induced pyroptotic vulnerability via the GSDME pathway in EGFR‑mutant lung cancer.","authors":"Wenwen Chang, Jiaxin Yuan, Huilin Zhang, Ying Yu, Yan Ma, Mingyue Li, Wenjing Li, Hongxia Yan, Chongran Sun, Peng Zhang, Yang Tian, Feng Guo, Pan Li, Yang Sun","doi":"10.3892/mmr.2026.14017","DOIUrl":"10.3892/mmr.2026.14017","url":null,"abstract":"<p><p>Drug‑tolerant persister cells represent a major barrier to durable responses in cases of epidermal growth factor receptor (EGFR)‑mutant lung adenocarcinoma treated with tyrosine kinase inhibitors. To define the molecular features and actionable vulnerabilities of this cell state, public transcriptomic datasets from tumour cell‑based models treated with EGFR inhibitors or other targeted agents within the receptor tyrosine kinase (RTK)/RAS/MAPK pathway were integrated with machine‑learning‑based feature selection, survival analysis and Cancer Dependency Map‑based pharmacogenomic screening. The present study also performed experimental validation of identified genes and drugs in PC‑9 and HCC827 cell models. A four‑gene persister‑associated gene signature comprising B‑cell translocation gene 1 protein, inhibitor of growth protein 4, proline‑rich nuclear receptor coactivator 1 and calcium‑binding and coiled‑coil domain‑containing protein 1 was identified, which defined a targeted therapy‑induced persister state and associated with poor patient survival. Functional validation using reverse transcription‑quantitative PCR, doxycycline‑inducible short hairpin RNA knockdown and β‑galactosidase staining assays demonstrated rapid induction of these genes during osimertinib treatment and showed that depletion of each gene markedly impaired drug‑tolerant persister cell formation. Pharmacogenomic analysis identified ZLN005, a peroxisome proliferator‑activated receptor γ coactivator‑1α agonist, as a candidate metabolic modulator that synergized with osimertinib to reduce persister cell viability. Mechanistically, ZLN005 enhanced mitochondrial oxidative metabolism and reactive oxygen species accumulation, leading to caspase‑3 activation and gasdermin E‑associated pyroptotic cell death. Collectively, these findings defined the transcriptional and metabolic features of targeted therapy‑induced persister cells and revealed a metabolic vulnerability to ZLN005 in EGFR‑mutant lung adenocarcinoma.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"34 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}