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000285918 1001_ $$0P:(DE-2719)9003386$$aLyu, Feng$$b0$$eFirst author$$udzne
000285918 245__ $$aSphingolipid-associated signature unveils TIMP1-driven temozolomide resistance and guides stratified therapy in glioblastoma.
000285918 260__ $$aLausanne$$bFrontiers Media$$c2026
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000285918 520__ $$aGlioblastoma (GBM) remains the most prevalent and aggressive primary central nervous system (CNS) malignancy; however, the clinical efficacy of the preferred chemotherapeutic agent, Temozolomide (TMZ), is severely compromised by innate and acquired resistance. Sphingolipid metabolism acts as a pivotal regulator of GBM cell fate, and the imbalance of the 'sphingolipid rheostat' is intimately linked to TMZ resistance. This provides potential targets for developing novel prognostic models to inform stratified treatment risk strategies, while offering a promising entry point for TMZ chemosensitization and stratified drug combinations.We integrated single-cell and bulk transcriptomics from TCGA and GEO. Through a multi-dimensional framework combining Weighted Gene Co-expression Network Analysis (WGCNA), differential expression profiling, Cox regression, and machine learning, we identified candidate genes associated with the molecular landscape coupled with sphingolipid dysregulation and TMZ sensitivity in GBM to construct a reliable prognostic model. We verified mRNA expression of model genes and protein expression of TIMP1 in clinical specimens via RT-qPCR and tissue microarrays (TMA), respectively. Furthermore, we functionally characterized the core target, TIMP1, via lentiviral knockdown in U87 cells, employing Transwell, CCK-8, and IC50 assays to evaluate its impact on malignancy and, crucially, its capacity to modulate TMZ chemosensitization.Single-cell analysis stratified GBM samples into distinct metabolic subclasses, revealing significant metabolic heterogeneity. Integrating TCGA and GEO profiles with WGCNA-based multi-dimensional intersection, we identified 95 candidate genes, refined via Cox regression and machine learning into a potent six-gene model (MXRA8, TIMP1, TREM1, S100A4, RMI2, IRF7) reflecting critical axes of extracellular matrix (ECM) remodeling, inflammation, and DNA repair. We delineated the model's role in shaping an immune-excluded tumor microenvironment (TME) characterized by stromal remodeling, T-cell exhaustion and functional impairment of natural killer (NK) cell subsets, while uncovering specific therapeutic vulnerabilities for distinct risk subgroups. Experimental validation confirmed widespread upregulation of core targets in clinical specimens. Functionally, TIMP1 knockdown significantly suppressed proliferation and invasion. Most importantly, silencing TIMP1 effectively restored sensitivity to TMZ (chemosensitization).This study establishes and validates a robust GBM prognostic model integrating the sphingolipid-associated molecular landscape with chemotherapy resistance. It provides a comprehensive perspective on the interplay among sphingolipid dysregulation, immune evasion, TMZ resistance, and the critical functional role of TIMP1. Beyond enabling precise patient stratification, this model highlights specific therapeutic vulnerabilities, offering a translational framework for developing combinatorial strategies to target the sphingolipid regulatory network and overcome GBM chemoresistance.
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000285918 650_7 $$2Other$$aTIMP1
000285918 650_7 $$2Other$$aglioblastoma
000285918 650_7 $$2Other$$apharmacogenomics
000285918 650_7 $$2Other$$aprognostic model
000285918 650_7 $$2Other$$asphingolipid metabolism
000285918 650_7 $$2Other$$atemozolomide resistance
000285918 650_7 $$2Other$$atumor microenvironment
000285918 650_7 $$2NLM Chemicals$$aSphingolipids
000285918 650_7 $$0YF1K15M17Y$$2NLM Chemicals$$aTemozolomide
000285918 650_7 $$2NLM Chemicals$$aTissue Inhibitor of Metalloproteinase-1
000285918 650_7 $$2NLM Chemicals$$aTIMP1 protein, human
000285918 650_7 $$2NLM Chemicals$$aAntineoplastic Agents, Alkylating
000285918 650_2 $$2MeSH$$aHumans
000285918 650_2 $$2MeSH$$aGlioblastoma: drug therapy
000285918 650_2 $$2MeSH$$aGlioblastoma: genetics
000285918 650_2 $$2MeSH$$aGlioblastoma: metabolism
000285918 650_2 $$2MeSH$$aGlioblastoma: pathology
000285918 650_2 $$2MeSH$$aSphingolipids: metabolism
000285918 650_2 $$2MeSH$$aTemozolomide: pharmacology
000285918 650_2 $$2MeSH$$aTemozolomide: therapeutic use
000285918 650_2 $$2MeSH$$aDrug Resistance, Neoplasm: genetics
000285918 650_2 $$2MeSH$$aTissue Inhibitor of Metalloproteinase-1: genetics
000285918 650_2 $$2MeSH$$aTissue Inhibitor of Metalloproteinase-1: metabolism
000285918 650_2 $$2MeSH$$aBrain Neoplasms: drug therapy
000285918 650_2 $$2MeSH$$aBrain Neoplasms: genetics
000285918 650_2 $$2MeSH$$aBrain Neoplasms: metabolism
000285918 650_2 $$2MeSH$$aGene Expression Regulation, Neoplastic
000285918 650_2 $$2MeSH$$aAntineoplastic Agents, Alkylating: pharmacology
000285918 650_2 $$2MeSH$$aAntineoplastic Agents, Alkylating: therapeutic use
000285918 650_2 $$2MeSH$$aCell Line, Tumor
000285918 650_2 $$2MeSH$$aPrognosis
000285918 650_2 $$2MeSH$$aGene Expression Profiling
000285918 650_2 $$2MeSH$$aTranscriptome
000285918 7001_ $$0P:(DE-2719)9003344$$aWu, Jingjing$$b1$$udzne
000285918 7001_ $$aQi, Ji$$b2
000285918 7001_ $$0P:(DE-2719)9002882$$aWang, Gege$$b3$$udzne
000285918 7001_ $$0P:(DE-2719)9002974$$aXie, Liqing$$b4$$udzne
000285918 7001_ $$0P:(DE-2719)9002782$$aWang, Zhicong$$b5$$eLast author$$udzne
000285918 773__ $$0PERI:(DE-600)2606827-8$$a10.3389/fimmu.2026.1753274$$gVol. 17, p. 1753274$$p1753274$$tFrontiers in immunology$$v17$$x1664-3224$$y2026
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