Comprehensive analysis of palmitoylation-related proteins for prognostic risk evaluation and tumor immune microenvironment assessment in glioma.

BACKGROUND: Glioma is one of the most common tumors, characterized by a high incidence rate and mortality, posing a formidable global health challenge. Palmitoylation represents a significant post-translational modification that holds a pivotal role in the progression of glioma. However, the biological mechanisms underlying palmitoylation-related genes (PRGs) in glioma remain elusive to date. METHODS: This study utilized an unsupervised clustering algorithm based on the TCGA-GBMLGG cohort to identify palmitoylation-related molecular subtypes and comparatively analyzed the differences between the two subtypes in terms of clinicopathological characteristics, tumor microenvironment (TME), response to immunotherapy, and somatic mutations. Subsequently, through LASSO Cox regression analysis, a palmitoylation-related risk score (PRRS) model for predicting the prognosis of glioma patients was developed and validated. Additionally, the differences in chemotherapeutic drug sensitivity and response to immunotherapy among different PRRS groups were evaluated. Ultimately, potential drugs targeting palmitoylation-related proteins for the treatment of glioma were explored through molecular docking studies, molecular dynamics simulations, and in vitro drug experiments. RESULTS: This study found that compared with glioma patients in Cluster 2, those in Cluster 1 had a higher World Health Organization (WHO) grade and a worse prognosis. Additionally, the infiltration levels of M2-type macrophages and regulatory T cells were higher in Cluster 1 than in Cluster 2. Immune checkpoint genes, major histocompatibility complex (MHC), and T-cell stimulators were also upregulated in Cluster 1. The PRRS model shows promising prospects in predicting the prognosis of glioma patients, and patients with lower PRRS values are more likely to benefit from immunotherapy. Molecular docking, molecular dynamics simulations, and in vitro drug experiments have confirmed that AT-7519, BIX02189, and THZ-2-101-1 can inhibit glioma cell migration while promoting cell apoptosis. CONCLUSIONS: A significant correlation exists between palmitoylation and tumor microenvironment in glioma. The PRRS emerges as a dependable prognostic biomarker, offering therapeutic advantages in the context of chemotherapy and immunotherapy, and potentially aiding in clinical decision-making for glioma patients. The identified compounds, AT-7519, BIX02189, and THZ-2-101-1, may potentially exert inhibitory effects on the malignant progression of glioma by targeting palmitoylation-related proteins.