# Determining the role of lipid droplets and their therapeutic potential in glioblastoma > **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $527,917 ## Abstract ABSTRACT Over the past two decades, the prognosis for glioblastoma (GBM), the most lethal brain tumor, has remained dismal, with a median survival of only 12-16 months from diagnosis. We recently demonstrated that GBM cells acquire large amounts of fatty acids (FAs) and cholesterol by dramatically upregulating their de novo synthesis and uptake for rapid tumor growth. However, excess FAs and cholesterol can alter membrane dynamics and function, leading to cellular damage. How GBM cells avoid this lipotoxicity to sustain proper lipid levels in different cellular compartments, particularly in the mitochondria, is poorly understood. During the past 5 years of funding, we have made great progress in understanding how GBM controls FA homeostasis. We demonstrated that GBM cells upregulate diacylglycerol acyltransferase 1 (DGAT1), allowing them to store abundant FAs as triacylglycerol-containing lipid droplets (LDs) to prevent excess FA accumulation to induce toxicity. In this renewal proposal, we will address two unanswered critical questions: 1) how is cholesterol homeostasis regulated in GBM cells? and 2) can effective therapeutic approaches be developed for GBM by disrupting lipid homeostasis? We recently found that cholesteryl esters (CEs), which form LDs to store excess cellular cholesterol, are largely present in GBM tissues, and blocking CE synthesis results in dramatic mitochondrial fragmentation in GBM cells. Moreover, our preliminary data showed that cholesterol is transferred from CE- containing LDs (CE-LDs) to the plasma membrane, while inhibition of autophagy blocks this transfer. These data suggest that CE-LDs maintain proper cellular cholesterol levels via autophagy. Our preliminary data further showed that stearoyl-CoA desaturase 1 (SCD1), which has been shown to prevent endoplasmic reticulum (ER) stress and ferroptosis, is upregulated upon DGAT1 inhibition. Finally, preliminary data showed that the expression of multiple antioxidant genes is significantly elevated in response to DGAT1 inhibition. These results strongly suggest that GBM cells can activate defense mechanisms to alleviate the lipotoxicity triggered by disruption of FA storage, possibly leading to tumor resistance to DGAT1 inhibition. Thus, we hypothesize that CE-LDs serve as critical reservoirs for controlling cholesterol homeostasis and mitochondrial function, and that combining disruption of storage or redistribution of cholesterol with interference with mitochondrial cholesterol import, or disruption of FA storage with either inhibition of SCD1 or blockade of antioxidant pathways are effective strategies for targeting GBM. In Aim 1, we will examine the impact of inhibiting cholesterol storage or redistribution from CE-LDs on cholesterol homeostasis and mitochondrial function, and whether such blockade can synergize with interfering in cholesterol import into mitochondria to efficiently kill tumor cells in GBM xenograft models. In Aim 2, we will examine whether inhibiti... ## Key facts - **NIH application ID:** 10886803 - **Project number:** 5R01NS104332-07 - **Recipient organization:** OHIO STATE UNIVERSITY - **Principal Investigator:** Deliang Guo - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $527,917 - **Award type:** 5 - **Project period:** 2018-09-15 → 2028-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10886803 ## Citation > US National Institutes of Health, RePORTER application 10886803, Determining the role of lipid droplets and their therapeutic potential in glioblastoma (5R01NS104332-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10886803. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*