Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.","authors":"Haowu Jiang, Wan Zhao, Hui Zhou, Rui Sun","doi":"10.1186/s13046-026-03767-7","DOIUrl":"10.1186/s13046-026-03767-7","url":null,"abstract":"<p><p>Glioblastoma (GBM) is one of the most aggressive and lethal primary brain tumors in adults, characterized by dynamic clonal evolution and extensive genomic, cellular, spatial, and microenvironmental heterogeneity. Multi-omics studies have revealed that GBM follows complex evolutionary trajectories involving genetic, epigenetic, transcriptional, and immune-microenvironmental remodeling as tumors grow, adapt to the brain microenvironment, and acquire therapeutic resistance. Increasing evidence suggests that GBM may originate from aberrant neural stem or progenitor cells, including those residing in the subventricular zone, and that glioblastoma stem cells (GSCs) contribute to tumor propagation, heterogeneity, and recurrence. A key conceptual challenge is to reconcile hierarchical cancer stem cell models, in which GSCs are viewed as relatively stable tumor-propagating subpopulations, with dynamic state plasticity models, in which stem-like properties can be reversibly acquired or lost during transitions among proneural-like, mesenchymal-like, invasive, and therapy-tolerant states. Recent advances in single-cell profiling, spatial transcriptomics, lineage tracing, organoid culture, 3D bioprinting, genetically engineered models, and artificial intelligence (AI)-assisted computational modeling have substantially improved the ability to study these processes. However, no currently available model fully recapitulates human GBM heterogeneity, recurrence, treatment history, and tumor-microenvironment interactions. Therefore, model selection should be guided by clearly defined mechanistic questions rather than by reliance on any single platform. This review summarizes current advances in in vitro, ex vivo, in vivo, and computational models for studying GBM evolution and heterogeneity, and discusses how integrated model pipelines may improve preclinical drug testing, treatment-response prediction, and precision neuro-oncology.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148354590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HES1 inhibition overcomes CDK4/6 inhibitor resistance by targeting cancer stemness in lung adenocarcinoma.","authors":"Alvin Ho Kwan Cheung, Kit Yee Wong, Gordon Yuan-Ho Li, Fuda Xie, Qiuqiu Wu, Thomas Tin Ho Yuen, Pak Lam Hui, Pingmei Huang, Xiaoli Liu, Bonan Chen, Fenfen Ji, Yujuan Dong, Alfred Sze-Lok Cheng, Calvin Sze Hang Ng, Xiang Zhang, Chi Chun Wong, Jun Yu, Wei Kang, Ka-Fai To","doi":"10.1186/s13046-026-03771-x","DOIUrl":"10.1186/s13046-026-03771-x","url":null,"abstract":"<p><strong>Background: </strong>CDK4 alterations are common in lung adenocarcinoma, but recent clinical trials only demonstrated modest therapeutic responses to CDK4/6 inhibitors. The mechanism of CDK4/6 inhibitor resistance has not been fully characterized.</p><p><strong>Methods: </strong>Patient-derived organoids and cell lines were tested for their sensitivity to CDK4/6 inhibitors. The drug resistance mechanism relating to stemness pathway was tested by in-vitro and in-vivo assays. Screening of small molecule library was performed to explore potential therapeutic agents that could potentiate the efficacy of CDK4/6 inhibitors.</p><p><strong>Results: </strong>CDK4/6 inhibitors could inhibit the growth of lung adenocarcinoma patient-derived organoids and cell lines, and its drug resistance was associated with HES1 overexpression. We identified the vital role of HES1 in promoting cancer cell stemness through SOX9 upregulation via the phosphorylation of transcription factor STAT3. Inhibition of HES1 impaired lung cancer spheroid formation, reduced stemness marker expression, and enhanced the sensitivity of the spheroids towards the CDK4/6 inhibitor palbociclib. Knockdown of SOX9 recapitulated the functional effect of HES1 inhibition, confirming its role as a downstream effector mediating the stemness properties of lung cancer cells. Screening of small molecules revealed VR23 as a potent HES1 inhibitor, and it could suppress lung cancer growth and patient-derived organoids in a synergistic manner with palbociclib in-vitro and in-vivo. Moreover, the pSTAT3 inhibitor napabucasin could also afford synergy with palbociclib as well, further confirming the therapeutic vulnerability conferred by the HES1-pSTAT3-SOX9 pathway in potentiating CDK4/6 inhibitors.</p><p><strong>Conclusions: </strong>Our findings revealed a signalling pathway in which lung adenocarcinoma regulates stemness and tumourigenesis through HES1, and the targeting of this pathway by VR23 or napabucasin supports further preclinical development for CDK4/6 inhibitor combination therapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148340210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From paradox to target: IFN-β hijacks MEK signaling to drive a cell death-evading dormant phenotype in colorectal cancer.","authors":"Yangyang Zhou, Haigang Geng, Yi Xu, Yanggang Hong, Bo Mei, Huanglei Wu, Xuanxuan Jin, Mengfan Ye, Yi Wang, Zan Shen, Zhigang Zheng, Zhenhua Zhu, Xiangchou Yang, Zizhen Zhang, Chunchao Zhu","doi":"10.1186/s13046-026-03768-6","DOIUrl":"10.1186/s13046-026-03768-6","url":null,"abstract":"<p><strong>Background: </strong>The high clinical recurrence rate of colorectal cancer (CRC) is driven by the survival of residual tumor cells that evade therapy-induced death by entering a dormant state. While dormancy is a recognized mechanism of treatment resistance, the molecular drivers governing this \"quiescent reservoir\" and its associated vulnerabilities remain poorly characterized, limiting the development of strategies to eradicate these dormant seeds.</p><p><strong>Methods: </strong>We developed a COAD-specific Dormancy Score (CADS) derived from NMF analysis of ~ 69,000 single cells to quantify and identify a dormant subpopulation at single-cell resolution. Mechanistically, the IFN-β/cDC1 axis and its downstream MEK/ERK dependency were validated using a GFP-p27K- dormancy reporter system, spatial transcriptomics, and CRISPR/Cas9-mediated Ifnar1 knockdown. Finally, the synergistic efficacy of anti-PD-1 combined with MEK inhibition (Trametinib) was evaluated in orthotopic CRC mouse models.</p><p><strong>Results: </strong>The CADS effectively identified a distinct dormant subpopulation in CRC characterized by profound G0/G1 arrest, enhanced stemness, and multi-drug resistance. We uncovered a novel evasion mechanism mediated by the hijacking of IFN-β signaling. Conventionally recognized for its anti-proliferative roles, IFN-β signaling is exploited by surviving tumor cells to enter a deep quiescent state. This phenotype acts as a biological reservoir that fuels intratumoral heterogeneity and underpins the relapse of colorectal tumors by conferring resistance to conventional cytotoxic regimens. Effective anti-PD-1 therapy paradoxically enriches this dormant population via an enhanced IFN-β-conventional type 1 dendritic cell (cDC1) axis. Mechanistically, IFN-β-induced dormancy depends on MEK/ERK pathway activity, which sustains survival while suppressing apoptosis. This creates a synthetic lethal vulnerability: MEK inhibition (e.g., Trametinib) synergizes with IFN-β to re-sensitize dormant cells to apoptosis. Consequently, combining Trametinib with anti-PD-1 therapy overcomes this evasion mechanism, eliminates the dormant subpopulation, remodels the immune microenvironment, and shows strong synergistic efficacy in preclinical models.</p><p><strong>Conclusion: </strong>Our work redefines an immune-cell death paradox, revealing how tumors exploit IFN-β to evade therapy. We propose CADS as a translational biomarker for identifying tumors reliant on this pathway and validate a mechanism-based combination therapy that selectively targets dormancy-associated death resistance, offering a promising strategy to improve CRC outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148341084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reciprocal signaling-metabolic crosstalk between fibroblasts and tumor cells drives cetuximab tolerance in head and neck cancers.","authors":"Engy Vigneron, Julie Vignau, Olivier Lowyck, Valentin Van den Bossche, Jérôme Ambroise, Yann Kieffer, Fatima Mechta-Grigoriou, Isabella Rizzi, Maria Virginia Giolito, Manon Desgres, Hannah Zaryouh, An Wouters, Antonella Mendola, Hajar Dahou, Marine Leclerc, Romain Boidot, Aurélien Warnant, Yvan Larondelle, Olivier Feron, Jean-Pascal Machiels, Sandra Schmitz, Cyril Corbet","doi":"10.1186/s13046-026-03765-9","DOIUrl":"10.1186/s13046-026-03765-9","url":null,"abstract":"<p><strong>Background: </strong>Resistance to EGFR-targeted therapies, including cetuximab, remains a major barrier to effective treatment of head and neck squamous cell carcinoma (HNSCC). Lipid metabolism reprogramming, TGFβ signaling, and cancer-associated fibroblast (CAF) activation have each been linked to cetuximab resistance, but how these processes mechanistically converge remains unclear.</p><p><strong>Methods: </strong>We integrated transcriptomic, metabolic, and biochemical assays in HNSCC cell lines, co-culture systems with matched patient-derived non tumoral fibroblasts and CAFs, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs) to characterize tumor-stroma interactions during cetuximab treatment. Fluorescence-based fatty acid (FA) tracing and lipidomic analyses were used to assess FA flux. Functional relevance was tested through genetic and pharmacologic inhibition of TGF-β2 signaling and FA transfer. Clinical relevance was assessed by analyzing TGFB2 expression and plasma TGF-β2 levels in HNSCC patient cohorts.</p><p><strong>Results: </strong>Cetuximab-treated HNSCC cells specifically upregulated and secreted TGF-β2, which induced two coordinated adaptive programs: (i) autocrine metabolic rewiring promoting FA uptake, oxidation, and storage in tumor cells, and (ii) paracrine activation of fibroblasts toward a myofibroblastic, lipid-secreting phenotype. These TGFβ2-activated CAFs supplied FA that sustained oxidative metabolism and preserved EGFR/MAPK signaling in tumor cells, establishing a reciprocal feedback loop that maintained a reversible drug-tolerant state. Disrupting either TGF-β2 signaling or FA transfer abrogated this circuit and restored cetuximab sensitivity in HNSCC cells, spheroids, and PDOs. In PDX models, TGF-β2 inhibition delayed tumor regrowth following cetuximab treatment. Elevated TGFB2 expression and circulating TGF-β2 levels were associated with metabolic reprogramming and poorer clinical outcomes following cetuximab therapy.</p><p><strong>Conclusions: </strong>Our findings define a tumor-stroma metabolic cooperation axis in which TGFβ2-driven lipid exchange sustains adaptive cetuximab tolerance in HNSCC. Targeting TGFβ2-mediated stromal reprogramming or FA transfer represents a promising strategy to delay or overcome resistance to EGFR-targeted therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148320297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting metabolic dependencies to reverse chemoradiotherapy resistance in colorectal cancer.","authors":"Maximilian Hellkamp, Simon Gertken, Jonas Buchloh, Julius-Leonard Hellwig, Lukas Ben Kowitzke, Ningjun Duan, Ilaria Gaspardo, Stefan Küffer, Michael Linnebacher, Philipp Ströbel, Matthias Wirth, Volker Ellenrieder, Stefan Rieken, Jochen Gaedcke, Michael Ghadimi, Jürgen Wienands, Günter Schneider, Melanie Spitzner, Marian Grade","doi":"10.1186/s13046-026-03755-x","DOIUrl":"10.1186/s13046-026-03755-x","url":null,"abstract":"<p><p>Neoadjuvant chemoradiotherapy (CRT) constitutes a standard treatment for locally advanced rectal cancer (RC), frequently followed by radical surgical resection. Yet, therapeutic responses vary widely, and intrinsic radioresistance remains a major barrier to cure. To uncover actionable determinants of CRT response, we established a panel of patient-derived colorectal cancer cell lines (PDCLs) followed by integrated phenotypic and functional characterization. We identified metabolic reprogramming as a hallmark of radioresistance and, through orthogonal validation experiments, confirmed elevated glycolytic and mitochondrial ATP production in (chemo)irradiation-resistant PDCLs. The causative relationship of this association and its potential for therapeutic intervention was shown by subsequent drug screening, showing resistance to most of the applied drugs and revealing a critical dependency on the monocarboxylate transporter (MCT1) and the glucose transporter 1 (GLUT1). Metabolism-targeting compounds re-sensitized resistant PDCLs to irradiation; especially inhibition of GLUT1 exhibits a robust radiosensitizing activity across models. Concordantly, GLUT1 expression correlated with poor response to neoadjuvant CRT in our own RC patient cohort and various publicly available patient datasets. Collectively, our study defines metabolic dependency as a key driver of CRT resistance in RC, and reveals glycolysis- and lactate-transport-associated pathway activities as targetable vulnerabilities. These findings provide a mechanistic basis for patient stratification and support the development of metabolism-directed strategies to overcome (chemo)radioresistance in RC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148310317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: MTA1 promotes metastasis of MPM via suppression of E-cadherin.","authors":"Caihua Xu, Fei Hua, Yihuan Chen, Haoyue Huang, Wenxue Ye, Yunsheng Yu, Zhenya Shen","doi":"10.1186/s13046-026-03750-2","DOIUrl":"10.1186/s13046-026-03750-2","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148310314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Vitexin compound 1, a novel extraction from a Chinese herb, suppresses melanoma cell growth through DNA damage by increasing ROS levels.","authors":"Nian Liu, Kuan Song Wang, Min Qi, Ying Jun Zhou, Guang Yao Zeng, Juan Tao, Jian Da Zhou, Jiang Lin Zhang, Xiang Chen, Cong Peng","doi":"10.1186/s13046-026-03761-z","DOIUrl":"10.1186/s13046-026-03761-z","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: TSP50 facilitates breast cancer stem cell‑like properties maintenance and epithelial‑mesenchymal transition via PI3K p110α mediated activation of AKT signaling pathway.","authors":"Feng Gao, Sichen Liu, Jing Wang, Gang Wei, Chunlei Yu, Lihua Zheng, Luguo Sun, Guannan Wang, Ying Sun, Yongli Bao, Zhenbo Song","doi":"10.1186/s13046-026-03760-0","DOIUrl":"10.1186/s13046-026-03760-0","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148273620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular immunotherapy in melanoma: the next frontier in cancer treatment.","authors":"Anna-Lena Wien, Angeliki Stamtsis-Datsi","doi":"10.1186/s13046-026-03762-y","DOIUrl":"10.1186/s13046-026-03762-y","url":null,"abstract":"<p><p>Therapy-resistant melanoma remains a major clinical challenge despite advances with immune checkpoint inhibitors and targeted therapies, as most patients ultimately exhibit primary or acquired resistance and progress through multiple toxic treatment lines with limited durable benefit. This resistance reflects not only T-cell dysfunction but also a profound quantitative deficit of tumor-reactive lymphocytes, compounded by myeloid- and T_reg-mediated immunosuppression, impaired antigen presentation, and tumor dedifferentiation programs generating a cold tumor microenvironment. Cellular immunotherapies aim to overcome these barriers by supplying or priming new tumor-reactive repertoires while reshaping the tumor microenvironment and restoring durable immunity. Dendritic-cell vaccines safely induce broad, long-lived responses but show modest activity as monotherapy in advanced disease. Tumor-infiltrating lymphocyte therapy directly replaces the missing tumor-specific compartment and has demonstrated clinically meaningful response rates in checkpoint-refractory melanoma, though at the cost of complex, intensive manufacturing and conditioning requirements. Genetically engineered TCR-T and CAR T/CAR NK therapies provide programmable specificity but remain constrained by antigen selection, toxicity risks, and limited persistence in solid tumors. NK-cell platforms offer HLA-independent, off-the-shelf potential but require further optimization for trafficking, persistence, and resistance to suppression. Overall, rational combinations - particularly DC-priming integrated with adoptive cell therapy - represent the most promising path to durable tumor control in treatment-refractory melanoma.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148279925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual regulation of metabolic reprogramming and protein competitive modifications: the core role and mechanism of MRPL36 in glioblastoma malignant progression.","authors":"Haonan Ye, Yuqi Wen, Zhihua Chen, Lei Wu, Zhe Zhang, Jie Zeng, Siyi Zhao, Bowen Fan, Bin Liao, Xinyu Tu, Zhangda Xiong, Lieliang Zhang, Youyi Xia, Jun Xie, Hong Zhu, Hua Guo, Feng Xiao","doi":"10.1186/s13046-026-03764-w","DOIUrl":"10.1186/s13046-026-03764-w","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) has an extremely poor prognosis. Abnormal mitochondrial function, metabolic disorders, and dysregulated ferroptosis all drive its malignant progression, and the underlying molecular regulatory mechanisms still need further clarification. This study focuses on the regulatory mechanisms linking mitochondrial function, lipid metabolism, and ferroptosis to provide new directions for clinical treatment.</p><p><strong>Methods: </strong>Bioinformatics analysis confirmed aberrant upregulation of mitochondrial ribosomal protein L36 (MRPL36) in GBM, correlating with poor prognosis. In vitro and in vivo assays validated its roles in regulating GBM cell proliferation and invasion. RNA sequencing and untargeted metabolomics were used to analyze molecular changes upon MRPL36 knockdown. Acyl-biotin exchange (ABE) assays examined MRPL36 regulation of zinc finger DHHC-type palmitoyltransferase 12 (ZDHHC12)-mediated glutathione peroxidase 4 (GPX4) palmitoylation. Co-immunoprecipitation (Co-IP), Western blotting and mass spectrometry (MS) characterized tripartite motif-containing 33 (TRIM33)-dependent K48-linked ubiquitination and proteasomal degradation of GPX4 under MRPL36 modulation. The molecular network driving GBM progression was ultimately clarified.</p><p><strong>Results: </strong>MRPL36 is highly expressed in GBM and associated with poor patient prognosis. Silencing MRPL36 exacerbates mitochondrial damage and disturbs lipid metabolism homeostasis. It suppresses ZDHHC12-mediated GPX4 palmitoylation, promotes TRIM33-mediated GPX4 K48-linked ubiquitination and degradation, induces ferroptosis in GBM cells, and markedly inhibits tumor proliferation, invasion, and in vivo growth. Ferroptosis inhibitors partially reverse these inhibitory effects, confirming that MRPL36 regulates GBM progression by balancing GPX4 palmitoylation and ubiquitination.</p><p><strong>Conclusion: </strong>This study confirms that MRPL36, as a key regulatory factor in GBM progression, maintains mitochondrial function and lipid metabolism homeostasis, modulates the balance between GPX4 palmitoylation (mediated by ZDHHC12) and ubiquitination (mediated by TRIM33), inhibits ferroptosis, and promotes GBM malignant progression, providing new targets and theoretical basis for GBM precise treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148279830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}