Chen Jun, Zuo Pin, Kuang Situo, Li Ping, Li Xiaoquan, Zhan Dong
Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital, Kunming, 650118, Yunnan, China.
Department of Human Anatomy, School of Basic Medical Sciences, Kunming Medical University, 1168 Chunrong West Road, Yuhua Street, Chenggong District, Kunming, 650500, Yunnan, China.
Biochem Genet. 2025 Aug 25. doi: 10.1007/s10528-025-11225-w.
Glioblastoma multiforme (GBM) is an aggressive brain tumor characterized by metabolic plasticity and resistance to therapy. Understanding the mechanisms underlying GBM's adaptability to metabolic stress is crucial for developing effective treatments. This study investigates the role of Brain Protein I3 (BRI3) in regulating lipid metabolism and autophagy in GBM, and its potential as a therapeutic target. We performed integrative bioinformatics analysis using TCGA-GBM and CGGA datasets to identify lipophagy-related gene signatures. BRI3's function was examined through in vitro studies using GBM cell lines and patient-derived samples. Lipid metabolism and autophagy were assessed under normal and oxygen-glucose deprivation (OGD) conditions in BRI3-knockdown and control GBM cells. Bioinformatics analysis revealed a lipophagy-related gene signature associated with poor prognosis in GBM. BRI3 emerged as a key upregulated gene in GBM, correlating with altered lipid homeostasis and enhanced autophagy. In vitro studies demonstrated that BRI3 knockdown led to lipid accumulation, impaired autophagy, reduced proliferation, and increased apoptosis in GBM cells. Under OGD conditions mimicking the tumor microenvironment, BRI3-depleted cells showed compromised lipid mobilization, autophagy induction, and cell survival compared to controls. Our findings suggest BRI3 as a critical regulator of lipophagy in GBM, enhancing tumor cell resilience to metabolic stress. This study provides insights into GBM's metabolic adaptability and identifies BRI3 as a potential therapeutic target for modulating tumor cell survival in the challenging glioblastoma microenvironment.
多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，其特征在于代谢可塑性和对治疗的抗性。了解GBM适应代谢应激的潜在机制对于开发有效的治疗方法至关重要。本研究调查了脑蛋白I3（BRI3）在调节GBM脂质代谢和自噬中的作用及其作为治疗靶点的潜力。我们使用TCGA-GBM和CGGA数据集进行了综合生物信息学分析，以识别与脂质自噬相关的基因特征。通过使用GBM细胞系和患者来源的样本进行体外研究来检验BRI3的功能。在BRI3敲低和对照GBM细胞的正常和氧-葡萄糖剥夺（OGD）条件下评估脂质代谢和自噬。生物信息学分析揭示了与GBM预后不良相关的脂质自噬相关基因特征。BRI3作为GBM中一个关键的上调基因出现，与脂质稳态改变和自噬增强相关。体外研究表明，BRI3敲低导致GBM细胞中脂质积累、自噬受损、增殖减少和凋亡增加。在模拟肿瘤微环境的OGD条件下，与对照相比，BRI3缺失的细胞显示脂质动员、自噬诱导和细胞存活受损。我们的研究结果表明BRI3是GBM脂质自噬的关键调节因子，增强了肿瘤细胞对代谢应激的恢复能力。本研究深入了解了GBM的代谢适应性，并将BRI3鉴定为在具有挑战性的胶质母细胞瘤微环境中调节肿瘤细胞存活的潜在治疗靶点。
