Transcriptomic Evidence Identifies Two TMBIM Subgroups with Opposing Prognostic Associations in Glioma

Gliomas are the most common and aggressive primary brain tumours, with glioblastoma (GB) exhibiting a poor prognosis and limited therapeutic response. Dysregulation of intracellular ion homeostasis, particularly Ca²⁺ signalling, has emerged as a key contributor to glioma progression. The transmembrane BAX inhibitor motif-containing (TMBIM) protein family regulates intracellular Ca²⁺ flux and cell survival; however, their role in glioma remains incompletely understood. Gene expression and clinical data from TCGA, CGGA, and Rembrandt cohorts were analysed to assess the association between TMBIM1-6 expression, tumour grade, and patient survival. Correlation analyses identified TMBIM-associated gene networks, followed by functional enrichment to characterise underlying biological processes and molecular functions. The TMBIM family members segregated into two distinct groups with opposing clinical associations. TMBIM1, TMBIM4, and TMBIM6 were upregulated and associated with poor survival, whereas TMBIM2, TMBIM3, and TMBIM5 were downregulated and associated with increased survival. Functional enrichment analyses revealed two conserved gene expression programmes: TMBIM1/4/6 are linked to membrane trafficking, metabolic and bioenergetic adaptation, while TMBIM2/3/5 are associated with cell cycle regulation and chromosomal instability. These findings uncover a previously unrecognised functional divergence within the TMBIM family in glioma. This bipartite organisation highlights TMBIM proteins as potential prognostic markers and suggests that selective targeting of specific TMBIM subgroups may improve therapeutic strategies.