285918 20260407160948.0 10.3389/fimmu.2026.1753274 doi pmid:41929516 pmid pmc:PMC13038958 pmc DZNE-2026-00364 English 610 Lyu, Feng P:(DE-2719)9003386 0 First author dzne Sphingolipid-associated signature unveils TIMP1-driven temozolomide resistance and guides stratified therapy in glioblastoma. Lausanne 2026 Frontiers Media article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1775570841_8448 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Glioblastoma (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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de TIMP1 Other glioblastoma Other pharmacogenomics Other prognostic model Other sphingolipid metabolism Other temozolomide resistance Other tumor microenvironment Other Sphingolipids NLM Chemicals Temozolomide YF1K15M17Y NLM Chemicals Tissue Inhibitor of Metalloproteinase-1 NLM Chemicals TIMP1 protein, human NLM Chemicals Antineoplastic Agents, Alkylating NLM Chemicals Humans MeSH Glioblastoma: drug therapy MeSH Glioblastoma: genetics MeSH Glioblastoma: metabolism MeSH Glioblastoma: pathology MeSH Sphingolipids: metabolism MeSH Temozolomide: pharmacology MeSH Temozolomide: therapeutic use MeSH Drug Resistance, Neoplasm: genetics MeSH Tissue Inhibitor of Metalloproteinase-1: genetics MeSH Tissue Inhibitor of Metalloproteinase-1: metabolism MeSH Brain Neoplasms: drug therapy MeSH Brain Neoplasms: genetics MeSH Brain Neoplasms: metabolism MeSH Gene Expression Regulation, Neoplastic MeSH Antineoplastic Agents, Alkylating: pharmacology MeSH Antineoplastic Agents, Alkylating: therapeutic use MeSH Cell Line, Tumor MeSH Prognosis MeSH Gene Expression Profiling MeSH Transcriptome MeSH Wu, Jingjing P:(DE-2719)9003344 1 dzne Qi, Ji 2 Wang, Gege P:(DE-2719)9002882 3 dzne Xie, Liqing P:(DE-2719)9002974 4 dzne Wang, Zhicong P:(DE-2719)9002782 5 Last author dzne 10.3389/fimmu.2026.1753274 Vol. 17, p. 1753274 PERI:(DE-600)2606827-8 1753274 Frontiers in immunology 17 2026 1664-3224 http://pub.dzne.de/record/285918/files/DZNE-2026-00364.pdf Restricted http://pub.dzne.de/record/285918/files/DZNE-2026-00364.pdf?subformat=pdfa pdfa Restricted Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)9003386 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 1 P:(DE-2719)9003344 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-2719)9002882 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)9002974 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)9002782 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 JCR StatID:(DE-HGF)0100 StatID FRONT IMMUNOL : 2022 2024-12-28 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2024-12-28 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2024-12-28 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2023-12-29T15:23:07Z DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2023-12-29T15:23:07Z Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Anonymous peer review 2023-12-29T15:23:07Z Creative Commons Attribution CC BY (No Version) LIC:(DE-HGF)CCBYNV V:(DE-HGF) DOAJ 2023-12-29T15:23:07Z DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2024-12-28 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2024-12-28 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2024-12-28 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2024-12-28 IF >= 5 StatID:(DE-HGF)9905 StatID FRONT IMMUNOL : 2022 2024-12-28 Article Processing Charges StatID:(DE-HGF)0561 StatID 2024-12-28 Fees StatID:(DE-HGF)0700 StatID 2024-12-28 I:(DE-2719)1013005 AG Ehninger Translational Biogerontology 0 journal EDITORS VDBINPRINT I:(DE-2719)1013005 UNRESTRICTED