The objective of this study is to investigate the aggressive infiltration of glioblastoma into adjacent brain tissue, considering its challenging prognosis. Initially classified as an intergenic non-coding RNA, we aim to elucidate the functional implications of LINC01138 in glioblastoma. Glioma grading was performed utilizing H&E staining, which unveiled distinct nuclear morphology in high-grade gliomas. The downregulation of LINC01138 in glioma tissues was corroborated through qRT-PCR and gel electrophoresis, concurrently identifying two previously unrecognized LINC01138 isoforms. Expression profiling of all four LINC01138 isoforms was executed in glioma cell lines (A172, SHG-44, U251, U87-MG). The impact of LINC01138 overexpression in U87-MG and U251 cells was evaluated for cell proliferation, migration, and invasion through cell counting, CCK-8 analysis, and Transwell assays. Furthermore, the suppression of LINC01138 in SHG-44 cells substantiated its involvement in fostering tumor malignancy. Transcriptome sequencing revealed the inhibitory influence of LINC01138 on IGF1 expression. These findings contribute to an enriched comprehension of glioma biology by exploring the engagement of LINC01138 through diverse methodologies, thereby elucidating its potential therapeutic significance. Our investigation elucidates the intricate involvement of LINC01138 in gliomas. High-grade gliomas are characterized by elevated cell density and distinctive nuclear features. LINC01138 demonstrates a substantial downregulation in glioma tissues, with the identification of two novel isoforms. The expression of all four LINC01138 isoforms is notably diminished in both glioma tissues and cell lines. Elevated expression of LINC01138 demonstrates inhibitory effects on tumor cell proliferation, migration, and invasion, while its downregulation exacerbates malignancy. The regulatory function of LINC01138 as a repressor of IGF1 expression was elucidated through transcriptome sequencing. The LINC01138 isoforms display notable tumor-suppressive effects, suggesting a promising potential for impeding glioma progression.

Glioblastoma (GBM) relapse and drug resistance are driven by a subset of quiescent, therapy-tolerant cells that persist in the G0 phase. However, the molecular mechanism coupling immune signaling to tumor cell quiescence and metabolic adaptation remains unclear. Multi-omics analyses of TCGA, CGGA, and GEO datasets, combined with single-cell transcriptomics and in vitro/in vivo experiments, were used to identify complement-related regulators of G0 maintenance. Genetic manipulation (shRNA/overexpression), pharmacological inhibition (C5AR1 antagonist JPE1375; STAT3 inhibitor Stattic), and rescue experiments with recombinant C3 were performed in glioma cell lines and xenograft models. Cell-cycle, mitochondrial, and redox states were assessed by flow cytometry, immunofluorescence, MitoTracker/MitoSOX staining, and ELISA. C5AR1 expression was markedly upregulated in GBM and correlated with poor prognosis (HR = 2.7, p = 6.4 × 10^-14). Single-cell and functional analyses revealed that C5AR1, activated by complement C3, sustains a spontaneous G0 population through JAK2/STAT3/STAT5 signaling. This axis enhanced mitochondrial integrity and oxidative phosphorylation, maintained low ROS homeostasis, and preserved stem-like features conferring chemoresistance. Knockdown or pharmacological blockade of C5AR1 disrupted G0-phase maintenance, decreased mitochondrial activity, and suppressed tumor growth in xenografts. C5AR1 inhibition also sensitized glioma cells to metabolic drugs by reversing rosiglitazone resistance and enhancing metformin efficacy. C5AR1 links extracellular complement activation to intracellular G0-phase maintenance and metabolic resilience in glioma. Targeting the C3-C5-C5AR1 axis disrupts quiescence-driven drug tolerance and represents a promising therapeutic strategy for overcoming chemoresistance in GBM.