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@ARTICLE{Lyu:285918,
      author       = {Lyu, Feng and Wu, Jingjing and Qi, Ji and Wang, Gege and
                      Xie, Liqing and Wang, Zhicong},
      title        = {{S}phingolipid-associated signature unveils {TIMP}1-driven
                      temozolomide resistance and guides stratified therapy in
                      glioblastoma.},
      journal      = {Frontiers in immunology},
      volume       = {17},
      issn         = {1664-3224},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DZNE-2026-00364},
      pages        = {1753274},
      year         = {2026},
      abstract     = {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.},
      keywords     = {Humans / Glioblastoma: drug therapy / Glioblastoma:
                      genetics / Glioblastoma: metabolism / Glioblastoma:
                      pathology / Sphingolipids: metabolism / Temozolomide:
                      pharmacology / Temozolomide: therapeutic use / Drug
                      Resistance, Neoplasm: genetics / Tissue Inhibitor of
                      Metalloproteinase-1: genetics / Tissue Inhibitor of
                      Metalloproteinase-1: metabolism / Brain Neoplasms: drug
                      therapy / Brain Neoplasms: genetics / Brain Neoplasms:
                      metabolism / Gene Expression Regulation, Neoplastic /
                      Antineoplastic Agents, Alkylating: pharmacology /
                      Antineoplastic Agents, Alkylating: therapeutic use / Cell
                      Line, Tumor / Prognosis / Gene Expression Profiling /
                      Transcriptome / TIMP1 (Other) / glioblastoma (Other) /
                      pharmacogenomics (Other) / prognostic model (Other) /
                      sphingolipid metabolism (Other) / temozolomide resistance
                      (Other) / tumor microenvironment (Other) / Sphingolipids
                      (NLM Chemicals) / Temozolomide (NLM Chemicals) / Tissue
                      Inhibitor of Metalloproteinase-1 (NLM Chemicals) / TIMP1
                      protein, human (NLM Chemicals) / Antineoplastic Agents,
                      Alkylating (NLM Chemicals)},
      cin          = {AG Ehninger},
      ddc          = {610},
      cid          = {I:(DE-2719)1013005},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41929516},
      pmc          = {pmc:PMC13038958},
      doi          = {10.3389/fimmu.2026.1753274},
      url          = {https://pub.dzne.de/record/285918},
}