Unlocking the secret of glioblastoma multiforme: the role of lactylation in tumor progression, drug resistance and immune microenvironment.

Background: Glioblastoma multiforme (GBM), the most prevalent and lethal type of brain cancer, is characterized by a poor prognosis despite advancements in comprehensive treatments, including surgery, chemotherapy, and radiotherapy. Lactylation, an emerging epigenetic modification, has been shown to influence the biological behavior of tumor cells; however, its role in GBM remains to be further elucidated.

Methods: In this study, we analyzed the relationship between lactylation-related genes (LRGs) and malignant biological behavior, temozolomide resistance, and the immune microenvironment of GBM using scRNA-seq data from public databases. Subsequently, we identified temozolomide-resistant lactylation-related genes (TMZR-LRGs) through differential gene expression analysis. Based on these genes, we proceeded to classify GBM subtypes and establish a risk prediction model to assess patient prognosis and treatment response. Finally, we validated the impact of lactylation on TMZ resistance and malignant biological behavior of GBM both in vivo and in vitro by knocking out UBE2E1 to increase cellular lactylation levels.

Result: ScRNA-seq analysis and in vivo and in vitro experiments both demonstrated that lactylation was significantly up-regulated in GBM cells. In the GBM subtype, MES-like cells have the highest lactylation level. Furthermore, an increase in lactylation levels enhanced the malignant proliferation and temozolomide resistance of GBM cells. The risk model based on TMZR-LRGs effectively predicted the prognosis and immune characteristics of GBM patients and had the potential to accurately identify targeted therapeutic drugs for GBM.

Conclusion: Lactylation is critical for malignant progression, temozolomide resistance and the establishment of an immunosuppressive microenvironment of GBM. The risk model based on lactylation-related genes is an effective tool for assessing the prognosis and treatment response of GBM patients. LRGs have potential as therapeutic targets for GBM, providing a new direction for improving patient outcomes.