HMGB1 mediates chemoresistance and tumor progression in glioblastoma: Implications for targeted therapy

Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor, characterized by rapid progression, high recurrence rates, and a median survival of less than 15 months despite current therapeutic interventions. Standard treatments such as surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy offer limited benefit due to the infiltrative nature of the tumor and the blood-brain barrier. Moreover, GBM frequently develops resistance to TMZ through O6-methylguanine-DNA methyltransferase (MGMT)-mediated repair of chemotherapy-induced DNA damage, significantly reducing treatment effectiveness. During treatment, GBM cells and the surrounding tumor microenvironment (TME) undergo significant physiological stress, including hypoxia, inflammation, and DNA damage. These stressors induce the release of damage-associated molecular patterns (DAMPs), among which High Mobility Group Box 1 (HMGB1) plays a pivotal role. HMGB1 is a multifunctional nuclear protein that, depending on its redox state and subcellular localization, can regulate tumor proliferation, invasion, angiogenesis, and immune modulation. Accumulating evidence suggests that extracellular HMGB1 contributes to tumor progression and therapeutic resistance through complex interactions with immune and stromal components of the TME. In our present study, we aim to validate the protumorigenic functions of HMGB1 using integrated bioinformatic approaches and in vitro analyses to substantiate its relevance in GBM pathology and therapy resistance. Specifically, we explored the correlation between HMGB1 expression and TMZ resistance, examining its association with MGMT expression and the activation of downstream signaling pathways, such as MEK1/2-ERK1/2. By elucidating these molecular interactions, we aim to clarify the mechanisms through which HMGB1 promotes therapy resistance. Additionally, we performed in-silico screening to identify HMGB1-targeting inhibitory compounds with the potential to concurrently suppress MGMT expression and other crucial components involved in TMZ resistance. Collectively, our findings aim to reinforce the significance of HMGB1 as a prognostic biomarker and therapeutic target, offering new opportunities for more effective and personalized treatment strategies for GBM patients.