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Lactate Metabolism-Immune Regulation-Related Gene Signature in Lower-Grade Gliomas: Prognostic Model Development and

Enhao Zhang1, Liangzhe Wei1, He Ren1

  • 1Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 18, 2026
PubMed
Summary

This study identifies a three-gene signature (VAV3, TNFRSF12A, PLA2G2A) to predict prognosis in low-grade gliomas (LGG). High-risk LGG patients show worse survival and altered immune profiles, with PLA2G2A validated as a potential therapeutic target.

Keywords:
PLA2G2Aimmune microenvironmentlactate metabolism‐immune regulation‐related geneslow‐grade gliomaprognostic modeltumor mutation burden

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Low-grade gliomas (LGG) exhibit variable prognoses, with lactate metabolism influencing the tumor immune microenvironment.
  • The prognostic role of lactate metabolism-associated genes in LGG remains unclear.

Purpose of the Study:

  • To identify and validate a prognostic gene signature for LGG based on lactate metabolism.
  • To investigate the relationship between this signature, immune infiltration, tumor mutational burden (TMB), and drug response.
  • To functionally validate the role of key genes, particularly PLA2G2A.

Main Methods:

  • Consensus clustering of TCGA and CGGA cohorts using lactate metabolism genes.
  • Development of a predictive model via differential analysis, Cox regression, and LASSO.
  • Evaluation of model associations with immune cells, TMB, and drug sensitivity.
  • Functional validation of PLA2G2A using molecular and in vivo assays.

Main Results:

  • Two distinct LGG subtypes with differing survival and immune profiles were identified.
  • A three-gene signature (VAV3, TNFRSF12A, PLA2G2A) accurately predicted high-risk vs. low-risk LGG patients.
  • High-risk LGG demonstrated reduced immune infiltration, increased TMB, poorer prognosis, and sensitivity to specific therapies.
  • PLA2G2A downregulation inhibited tumor growth, proliferation, migration, invasion, and reversed epithelial-mesenchymal transition.

Conclusions:

  • A novel three-gene prognostic model for LGG, reflecting metabolic-immune interactions, has been developed and validated.
  • This model accurately predicts patient prognosis and identifies potential therapeutic targets.
  • PLA2G2A is a promising therapeutic biomarker for LGG, with functional roles in tumor progression.