Frontiers in Molecular Biosciences最新文献

{"title":"Functions and mechanisms of miR-650 in human diseases.","authors":"Qingmiao Shi, Chengran Gao, Chen Xue","doi":"10.3389/fmolb.2026.1911030","DOIUrl":"10.3389/fmolb.2026.1911030","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are endogenous, single-stranded, small non-coding RNAs that play central roles in gene expression regulation. Among them, miR-650 has received increasing attention over the past decade because it regulates cell proliferation, differentiation, apoptosis, metabolism, cell cycle control, immune responses, and development. miR-650 has been studied in both neoplastic and non-neoplastic disease contexts. This review summarizes the expression characteristics of miR-650 in human diseases and discusses its roles in disease initiation and progression, the pathways in which it participates, and the upstream and downstream regulatory mechanisms involved. We also discuss the potential clinical value of miR-650 in disease diagnosis and therapy. Defining shared pathways across diseases and disease-subtype-specific expression patterns within miR-650-related regulatory networks may help identify more precise therapeutic targets.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1911030"},"PeriodicalIF":4.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149059765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA expression profile associated with coronary heart disease in patients with resistant arterial hypertension.","authors":"Robert Tomasz Błaszczyk, Alicja Petniak, Jacek Bogucki, Janusz Kocki, Łukasz Wiśniowski, Andrzej Głowniak","doi":"10.3389/fmolb.2026.1905966","DOIUrl":"10.3389/fmolb.2026.1905966","url":null,"abstract":"<p><strong>Background: </strong>Resistant arterial hypertension (RAH) is associated with a high burden of cardiovascular complications, particularly coronary heart disease (CHD). MicroRNAs (miRNAs) are important regulators of cardiovascular remodeling and metabolic dysfunction; however, data regarding peripheral blood mononuclear cell (PBMC) miRNA expression in patients with RAH and concomitant CHD remain limited. This study aimed to evaluate PBMC miRNA expression profiles associated with CHD in patients with RAH and to explore their relationship with metabolic abnormalities.</p><p><strong>Methods: </strong>In this cross-sectional study, 115 patients with RAH were enrolled. PBMCs were isolated from peripheral blood and expression levels of selected microRNAs were quantified using TaqMan-based quantitative real-time PCR. Relative expression was calculated using the 2^-ΔΔCT method and expressed as log-transformed relative quantification (logRQ). Patients were stratified according to the presence of CHD. Correlation analyses, subgroup comparisons, and receiver operating characteristic (ROC) analyses were performed.</p><p><strong>Results: </strong>Compared with patients with isolated RAH, those with concomitant CHD exhibited significantly higher PBMC expression levels of miR-195 (p = 0.0148), miR-26b (p = 0.0166), miR-208 (p = 0.0435), and miR-320 (p = 0.0402). These microRNAs demonstrated strong positive intercorrelations, indicating a coordinated expression pattern. Within the CHD subgroup, expression levels of all four microRNAs were significantly higher in patients with type 2 diabetes (T2D) and positively correlated with glycated hemoglobin and body mass index. ROC analysis demonstrated modest discriminative ability for identifying T2D within the CHD subgroup, with the highest performance observed for miR-195 (AUC = 0.706).</p><p><strong>Conclusion: </strong>Patients with RAH and concomitant CHD exhibit a distinct PBMC microRNA expression profile characterized by increased expression of miR-195, miR-208, miR-26b, and miR-320. The association of these microRNAs with T2D and markers of metabolic dysfunction suggests that they may reflect the combined cardiovascular and metabolic disease burden in patients with advanced hypertension.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1905966"},"PeriodicalIF":4.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149037467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune remodeling in chronic prostatitis: from microenvironment imbalance to targeted therapy.","authors":"Fulin Ma, Shiwei Song, Bin Zhang, Changfeng Yang, Chang Yu, Jinlong Yin, Linqi Liu, Dehui Chang","doi":"10.3389/fmolb.2026.1876056","DOIUrl":"10.3389/fmolb.2026.1876056","url":null,"abstract":"<p><p>Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) imposes a substantial clinical burden through persistent pelvic pain, lower urinary tract symptoms, sexual and reproductive dysfunction, recurrence, and variable responses to empirical therapy. Although infection, pelvic floor dysfunction and neurogenic mechanisms remain relevant, accumulating evidence indicates that persistent immune remodeling and inflammatory microenvironmental imbalance provide a unifying framework for disease chronicity. This narrative review synthesizes current evidence linking epithelial and stromal stress, ROS accumulation, cytokine and chemokine networks, NF-κB, JAK/STAT, NLRP3, HMGB1, HIF-1α and CXCR4 signaling with macrophage reprogramming, Th17/Treg imbalance, myeloid-derived suppressor cell activity and neuroimmune pain. Rather than treating these events as isolated pathways, we emphasize their crosstalk within a self-sustaining inflammatory circuit that connects local tissue injury with systemic metabolic and microbiota signals. We also discuss controversies surrounding IL-10 expression, immune-event causality and the limited direct evidence for immune-cell subset heterogeneity in CP/CPPS. Future work should integrate longitudinal cohorts, single-cell and spatial multi-omics, immune phenotyping and mechanism-oriented clinical trials to move CP/CPPS management from symptom control toward stratified immune intervention.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1876056"},"PeriodicalIF":4.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma miR-98-5p as a candidate biomarker of pain severity in oxaliplatin-induced peripheral neuropathy related to NGF and catecholamine dysregulation.","authors":"Yeongdon Ju, Go-Eun Choi, Aelee Jang","doi":"10.3389/fmolb.2026.1884789","DOIUrl":"10.3389/fmolb.2026.1884789","url":null,"abstract":"<p><strong>Background: </strong>Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and severe adverse event in patients with gastrointestinal (GI) cancer who undergo oxaliplatin-based chemotherapy. Assessments remain largely dependent on a numeric rating scale (NRS), which is needed for early detection and objective quantification of pain intensity.</p><p><strong>Methods: </strong>This study aimed to identify differentially expressed microRNAs (miRNAs) in plasma samples from 22 patients with GI cancer treated with oxaliplatin to elucidate the association between candidate miRNA expression levels, nerve growth factor (NGF), catecholamines, and NRS scores for peripheral neuropathic pain. High-throughput RNA sequencing was used to analyze miRNA expression profiles, and patients were stratified into Groups 1 (<i>n</i> = 10, no or mild pain) and 2 (<i>n</i> = 12, moderate or severe pain) based on their NRS scores. Correlations between variables were assessed using Spearman's rank-order correlation (r = 0.4031, <i>P</i> = 0.0629).</p><p><strong>Results: </strong>In Group 2, hsa-miR-98-5p was significantly upregulated and demonstrated the greatest potential to stratify patients by pain severity among the candidate miRNAs (The area under the curve = 0.8083, 95% CI: 0.6222-0.9944). Gene ontology enrichment analysis revealed that hsa-miR-98-5p was significantly associated with critical neuronal injury and repair signaling pathways. Patients in Group 2 exhibited decreased norepinephrine and dopamine levels, elevated NGF levels, and elevated cortisol levels, indicating potential alterations in the OIPN neuromodulatory systems.</p><p><strong>Conclusion: </strong>These findings suggest that miR-98-5p is a candidate biomarker of pain severity in OIPN and may play a role in OIPN pathophysiology.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1884789"},"PeriodicalIF":4.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13593450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction and verification of a nomogram to predict the probability of venous thromboembolism in lung cancer patients.","authors":"Rong Deng, Jing Wu, Fei Tang, Yan Li, Qin Zhong, Ying Tong, Tingting Ni, Yu Zhang","doi":"10.3389/fmolb.2026.1671697","DOIUrl":"10.3389/fmolb.2026.1671697","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer (LC) patients account for 20% of all cancer-related venous thromboembolism (VTE) events, which is the second leading cause of mortality in these patients. However, there are no LC-specific risk scores for VTE prediction. Therefore, we considered that an LC-specific nomogram would more accurately predict VTE probability for these patients than the current widely used VTE risk scores.</p><p><strong>Methods: </strong>A total of 676 patients from the Guizhou Provincial People's Hospital (January 2016 to September 2021) were included in this study, of which 169 LC patients who developed VTE were time-matched with 507 (1:3 ratio) LC patients without VTE. These patients were randomly divided at a 2:1 ratio to form primary (451) and validation (225) cohorts. The accuracy of six VTE risk scores was assessed by producing area under the receiver operating characteristic (ROC) curves (AUC). A multivariate analysis was employed to select predictive features, which were then used to construct a nomogram for VTE prediction.</p><p><strong>Results: </strong>Among the scoring methods, COMPASS-CAT had the highest AUC (0.799). The multivariate analyses revealed that acute infection, bed rest (>3 days), D-dimer level >1.47 μg/mL, adenocarcinoma, and carcinoembryonic antigen (CEA) >10.935 ng/mL were independent predictors of VTE risk for LC patients. The nomogram constructed using these factors enabled VTE prediction with a concordance index of 0.882 and an AUC of 0.894.</p><p><strong>Conclusion: </strong>This article describes the construction and validation of a new nomogram for VTE prediction in LC patients, which has a predictive performance that is higher than any of the widely used conventional risk assessment tools.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1671697"},"PeriodicalIF":4.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13585574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotypic distribution and molecular spectrum of rare and novel thalassemia variants in Ganzhou, southern China.","authors":"Jungao Huang, Xiaoyan Huang, Xinxing Xie, Xiaoqin Xin","doi":"10.3389/fmolb.2026.1833133","DOIUrl":"10.3389/fmolb.2026.1833133","url":null,"abstract":"<p><strong>Background: </strong>Thalassemia is the most common single-gene inherited blood disorder worldwide, being relatively rare in northern China but more prevalent in southern China. To facilitate effective prevention and control of thalassemia, we analyze the genotype and frequency distribution of rare thalassemia variants in the general population of the Ganzhou area, offering valuable insights for genetic counseling and prenatal diagnosis.</p><p><strong>Methods: </strong>Between January 2022 and January 2025, a cohort of 84,067 individuals was screened in Ganzhou. Following the exclusion criteria, 1,081 participants with rare thalassemia variants were included in the final analysis. Genotypes associated with thalassemia were determined using next-generation sequencing (NGS). Variant classification adhered to ACMG/AMP guidelines.</p><p><strong>Results: </strong>Among the participants with rare thalassemia variants, 495 individuals presented with rare α-thalassemia variants and 560 with rare β-thalassemia variants, including 26 newly identified variants. Rare thalassemia variants accounted for 1.29% of the total screened population. The distribution of rare thalassemia variants exhibited regional variation across Ganzhou, with the highest rates in Nan Kang (12.69%), followed by Xingguo (10.49%) and Zhanggong (8.80%). Chongyi had the lowest rate at 1.78%, with all these locations located to the northwest of Ganzhou. Additionally, 26 individuals carried novel thalassemia variants. Six of these variants were classified as \"Likely Pathogenic,\" and the HBB:c.50G>T (Gly > Val) genotype was associated with hypochromic anemia.</p><p><strong>Conclusion: </strong>This study offers a comprehensive analysis of rare and newly identified thalassemia variants in the Ganzhou area, highlighting the complexity and heterogeneity of the condition. These findings underscore the necessity for effective screening methods in regions with a high incidence of thalassemia and provide essential insights for the targeted prevention and management of this disorder in the future.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1833133"},"PeriodicalIF":4.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13581918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia-neuron communication in ischemic stroke: from homeostatic signaling to pathological remodeling and therapeutic targeting.","authors":"Sijie Liu, Hao Huang, Jian Xiong, Shuhong Yu, Yi Luo, Biao Zhang","doi":"10.3389/fmolb.2026.1910699","DOIUrl":"10.3389/fmolb.2026.1910699","url":null,"abstract":"<p><p>Ischemic stroke profoundly disrupts the homeostatic dialogue between microglia and neurons, converting a physiological surveillance network into a dynamic, injury-responsive, and spatially heterogeneous communication system. Under physiological conditions, neurons regulate microglia through diverse signaling pathways, while microglia support neuronal health via synaptic remodeling, inflammatory regulation, metabolic balance, and debris clearance. Following cerebral ischemia, cascades involving excitotoxicity, energy failure, ionic imbalance, damage-associated molecular patterns (DAMPs), complement activation, and cell death signals rapidly reprogram this bidirectional communication. In this Review, we propose the Microglia-Neuron Communication Continuum (MNCC) model as a conceptual framework for understanding post-stroke microglia-neuron crosstalk. The MNCC model conceptualizes these interactions as a multidimensional continuum defined by three core axes: time, communication mode, and functional outcome. Along the temporal axis, crosstalk evolves from the hyperacute and acute phases to the subacute and chronic stages. Along the communication-mode axis, interactions span direct contact-dependent mechanisms and indirect soluble signaling pathways. Along the functional-output axis, the biological consequences range from damage amplification to tissue repair and chronic maladaptation. Using this framework, we first summarize the physiological basis of bidirectional microglia-neuron signaling under homeostatic conditions. We then examine how ischemic stroke reprograms this network across distinct temporal stages and spatial niches, emphasizing that post-stroke crosstalk is a continuous, context-dependent, spatially heterogeneous, and functionally plastic process. Finally, we discuss current and emerging therapeutic strategies through the lens of the MNCC model, focusing on temporal matching, dominant communication modes, regional heterogeneity, and translational barriers. A deeper understanding of this communication continuum may facilitate the development of targeted interventions that restrain harmful signaling, preserve beneficial interactions, and ultimately improve long-term neurological recovery after ischemic stroke.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1910699"},"PeriodicalIF":4.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental dysfunction drives fetal growth restriction: mechanisms and translational perspectives.","authors":"Ling He, Dan Hong, Huan Chen, Xiangyi Chen","doi":"10.3389/fmolb.2026.1847608","DOIUrl":"10.3389/fmolb.2026.1847608","url":null,"abstract":"<p><p>Fetal growth restriction (FGR) is a major obstetric complication characterized by the inability of the fetus to reach its genetic growth potential, most commonly due to placental insufficiency. It contributes substantially to perinatal morbidity, stillbirth, and long-term cardiometabolic disease. Emerging evidence indicates that FGR arises not from a single defect but from a convergent, self-reinforcing network of placental dysfunction involving impaired trophoblast invasion, defective spiral artery remodeling, oxidative stress, angiogenic imbalance, immune dysregulation, nutrient transport failure, and epigenetic reprogramming. In early-onset FGR, hypoxia-driven HIF-1α signaling serves as an important integrating node linking angiogenic, inflammatory, and metabolic dysfunction, whereas additional HIF-1α-independent pathways appear to contribute more prominently in late-onset disease. Advances in single-cell and multi-omics technologies have refined the cellular and molecular landscape of the placenta, revealing complex intercellular interactions and regulatory circuits underlying disease heterogeneity. Clinically, diagnosis relies on integrated assessment of fetal biometry, Doppler velocimetry, and biomarkers such as the sFlt-1/PlGF ratio, while management remains largely surveillance-based with limited effective therapeutic options once placental dysfunction is established. Translational research is increasingly focused on precision approaches, including multi-omics biomarker panels, machine learning-based risk prediction, and pathway-targeted interventions. However, clinical implementation remains constrained by biological heterogeneity and lack of standardized validation. This review synthesizes current mechanistic insights and highlights emerging diagnostic and therapeutic strategies, emphasizing the need to shift from single-pathway models toward network-based and mechanism-stratified approaches. Advancing toward precision obstetrics will require integration of molecular profiling with clinical decision-making to improve outcomes for pregnancies affected by FGR.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1847608"},"PeriodicalIF":4.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poor prognosis of acute kidney injury superimposed on chronic kidney disease: potential mechanisms, risk factors and novel biomarkers.","authors":"Linmei Gao, Yuming Ding, Yanru Zhao, Yi Chen, Tao Liu, Wentong Lin, Bo Yang","doi":"10.3389/fmolb.2026.1879518","DOIUrl":"10.3389/fmolb.2026.1879518","url":null,"abstract":"<p><p>Acute kidney injury superimposed on chronic kidney disease (acute-on-chronic kidney injury, hereinafter referred to as AoCKI) is a common clinical syndrome with a generally poor prognosis compared to isolated acute kidney injury (AKI). Patients with AoCKI often face significantly heightened mortality, increased dependence on renal replacement therapy (RRT), and reduced likelihood of renal function recovery. Crucially, the pathophysiological mechanism of AoCKI is not merely an additive effect of two separate conditions, but a distinct synergistic insult driven by pre-existing microvascular and metabolic vulnerabilities. While recent clinical epidemiological studies have enhanced understanding of AoCKI, the mechanisms underlying its poor prognosis remain insufficiently elucidated, and research on population-specific biomarkers is limited. Most currently available biomarkers were identified in patients with isolated AKI and have not been specifically studied in the context of CKD. This review synthesizes previous findings and relevant research to examine the risk factors for AoCKI, as well as the potential pathophysiological mechanisms and biomarkers associated with impaired renal adaptive repair. The objective is to inform the development of more effective preventive measures, diagnostic criteria, and treatment strategies to improve outcomes for this patient population.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1879518"},"PeriodicalIF":4.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13584188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming-related drug resistance in osteosarcoma: from molecular mechanisms to therapeutic translation.","authors":"Qun Wu, Hongxiang Chen, Jian Li","doi":"10.3389/fmolb.2026.1928880","DOIUrl":"10.3389/fmolb.2026.1928880","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma remains the most prevalent primary malignant bone tumor in adolescents and young adults. For patients with localized disease, 5-year overall survival reaches 60%-70%; however, for those with metastatic or recurrent disease, 5-year survival remains stagnant at approximately 20%, and chemoresistance represents the primary obstacle to improved outcomes.</p><p><strong>Objective: </strong>This review systematically elucidates the crosstalk among glycolytic, lipid, and glutamine pathways and their synergistic interactions with the immune microenvironment in driving osteosarcoma drug resistance, while evaluating the translational potential of metabolic targeted therapies.</p><p><strong>Results: </strong>We highlight that aerobic glycolysis-derived histone lactylation, which has been shown to activate multidrug resistance gene transcription in other cancers and represents a candidate epigenetic mechanism warranting investigation in osteosarcoma; SCD1-mediated monounsaturated fatty acid synthesis confers ferroptosis resistance; glutamine-derived α-KG supports epigenetic programming and redox homeostasis; and metabolic competition creates an immunosuppressive tumor microenvironment. We further discuss metabolic heterogeneity, plasticity, and metabolomic methodologies as applied to osteosarcoma.</p><p><strong>Conclusion: </strong>Single-agent metabolic inhibitors show limited clinical efficacy due to metabolic plasticity and compensatory activation. Almost all metabolic targeting evidence remains preclinical; no metabolic therapy has yet entered standard osteosarcoma care. Triple combination strategies (metabolic inhibitors + immunotherapy + chemotherapy) represent a mechanistically attractive but clinically untested hypothesis. Telaglenastat (CB-839), a glutaminase inhibitor, has been prioritized for osteosarcoma clinical trials but efficacy data in osteosarcoma patients remain pending.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"13 ","pages":"1928880"},"PeriodicalIF":4.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13574613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}