Key Prognostic Genes and Histone Lactylation in Glioblastoma

Background on Glioblastoma and Histone Lactylation

Glioblastoma (GBM) is recognized as one of the most aggressive malignancies of the central nervous system, classified as a grade IV astrocytoma by the World Health Organization (WHO). Its incidence is approximately 3.21 cases per 100,000 individuals annually, accounting for around 57% of all gliomas and 48% of primary malignant brain tumors (Ostrom et al., 2021). The prognosis for GBM patients remains dismal, with a median survival of approximately 15 months despite extensive treatment interventions, including surgical resection, chemotherapy, and radiotherapy (Tan et al., 2020).

Histone lactylation, a post-translational modification, has emerged as a significant player in the regulation of gene expression and cancer biology. This modification involves the addition of a lactoyl group derived from lactate to lysine residues on histones, influencing chromatin structure and gene accessibility (Wang et al., 2023). In the context of GBM, histone lactylation has been linked to metabolic reprogramming and immune modulation within the tumor microenvironment (Peng et al., 2024). The accumulation of lactate in the tumor microenvironment not only fuels tumorigenesis but also contributes to immune suppression, creating a challenging landscape for effective therapeutic interventions.

Impact of Histone Lactylation on Glioblastoma Progression

Recent studies have demonstrated that elevated levels of histone lactylation are associated with poor prognosis in GBM patients. The Warburg effect, characterized by increased aerobic glycolysis in tumor cells, leads to higher lactate production, which in turn promotes histone lactylation (Li et al., 2022). The subsequent modifications of histones can enhance the expression of genes associated with tumor growth and survival, thereby facilitating GBM progression.

Histone lactylation appears to play a critical role in modulating the immune landscape of GBM. Elevated lactate levels can promote the polarization of tumor-associated macrophages towards an immunosuppressive phenotype, which is detrimental to anti-tumor immunity (Colegio et al., 2014). This immunosuppression is further exacerbated by the lactylation of histones, which can drive the expression of immune checkpoint molecules, leading to reduced T cell activation and impaired immune surveillance (Yang et al., 2022).

Identification of Prognostic Genes Associated with HLM

An integrated analysis of transcriptomic data has identified several histone lactylation modification-related genes (HLMRGs) that are potential prognostic markers in GBM. In a comprehensive study involving The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets, a total of 227 differentially expressed HLMRGs were identified, with significant associations to GBM progression (He et al., 2025). Among these, five key genes—SNCAIP, TMEM100, NLRP11, HOXC11, and HOXD10—exhibited strong prognostic potential, correlating with patient survival outcomes.

The prognostic risk model developed from these genes demonstrated robust predictive capabilities, with high-risk patients showing significantly poorer survival rates compared to low-risk patients (AUC > 0.6) (He et al., 2025). Notably, HOXC11 and HOXD10 were associated with poor prognosis, suggesting their roles in promoting GBM progression, while SNCAIP, TMEM100, and NLRP11 were linked to better outcomes, indicating potential tumor-suppressive functions.

Role of Immune Microenvironment in Glioblastoma

The immune microenvironment within GBM is characterized by a complex interplay between various immune cells, including microglia, macrophages, and T cells. Research indicates that lactate, a key metabolite produced under hypoxic conditions, can significantly influence immune cell behavior and function. Elevated lactate levels are associated with increased infiltration of immunosuppressive cell types, such as regulatory T cells (Tregs), which contribute to the immune evasion of tumors (Mendler et al., 2022).

Tumor-associated macrophages (TAMs) are pivotal in shaping the immune landscape of GBM. Lactate produced by tumor cells can drive the polarization of macrophages towards a pro-tumorigenic phenotype, exacerbating the immunosuppressive microenvironment (Zhao et al., 2022). The dysregulation of immune responses in GBM, coupled with high levels of histone lactylation, creates a formidable barrier against effective immunotherapy, highlighting the need for innovative treatment strategies targeting both metabolic and immunological pathways.

Potential Therapeutic Strategies Targeting HLMRGs

Given the promising prognostic value of HLMRGs in GBM, there is a critical need to explore therapeutic strategies that can effectively target these genes and their associated pathways. Potential strategies may include:

1. Targeting Metabolic Pathways: Inhibitors of lactate production or lactate dehydrogenase could potentially reduce histone lactylation and its associated oncogenic effects. Drugs like ATRA and cantharidin have shown promise in modulating lactate levels and improving therapeutic responses (He et al., 2025).

2. Immunotherapy Approaches: Combining immunotherapies with agents that target lactate metabolism may enhance anti-tumor immunity. For instance, therapies that inhibit Treg function or enhance Th1 responses in the context of high lactate levels could improve patient outcomes.

3. Gene Editing Technologies: CRISPR/Cas9 technology holds potential for directly modifying the expression of HLMRGs, offering a novel approach to manipulate the tumor microenvironment and restore effective immune responses against GBM.

4. Personalized Medicine: Utilizing patient-specific data to tailor therapies based on individual HLMRGS profiles may improve treatment efficacy and reduce toxicity. Developing nomograms that integrate HLMRGS with clinical characteristics can guide therapeutic decisions.

Conclusion

The exploration of histone lactylation and its associated prognostic genes in glioblastoma provides essential insights into the complex interplay between metabolism and immune regulation in tumor progression. The identification of key HLMRGs offers a foundation for developing targeted therapies that may improve patient management and outcomes. By integrating metabolic interventions with immunotherapeutic strategies, there is significant potential to overcome the challenges posed by GBM and enhance therapeutic efficacy.

FAQ

What is glioblastoma?
Glioblastoma (GBM) is the most aggressive type of primary brain tumor, classified as a grade IV astrocytoma, with poor prognosis and limited treatment options.

What is histone lactylation?
Histone lactylation is a post-translational modification involving the addition of a lactoyl group to histones, which can influence gene expression and cancer progression.

How do histone lactylation levels affect GBM prognosis?
Elevated levels of histone lactylation in GBM are associated with poor patient survival outcomes, indicating its potential as a prognostic biomarker.

What are HLMRGs?
Histone lactylation modification-related genes (HLMRGs) are genes associated with histone lactylation that have been identified as potential prognostic markers in glioblastom What therapeutic strategies are being explored to target HLMRGs?
Therapeutic strategies include targeting metabolic pathways, combining immunotherapies with lactate metabolism inhibitors, utilizing gene editing technologies, and implementing personalized medicine approaches.

References

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