Abstract B049: Metabolic reprogramming in glioma: Targeting fatty acid oxidation via malonyl-CoA decarboxylase (MLYCD) inhibition

Abstract Glioblastoma (GBM) is the most common primary brain cancer, defined by its infiltrative nature and resistance to traditional therapies, including surgery, radiation treatment, and chemotherapy. Despite therapeutic advances, GBM remains highly lethal, highlighting the urgent need for new metabolic-based treatment strategies. Growing evidence indicates that GBM cells extensively reprogram their metabolism to generate sufficient energy and adapt to nutrient-limited or hypoxic environments. Recent studies have highlighted fatty acid oxidation (FAO) as an essential metabolic pathway contributing to energy production in GBM. The reliance of GBM on FAO provides a rationale for targeting lipid catabolism. Malonyl-CoA decarboxylase (MLYCD) is a key enzymatic regulator at the intersection of fatty acid synthesis and oxidation. By converting malonyl-CoA into acetyl-CoA, MLYCD lowers malonyl-CoA levels and relieves inhibition of carnitine palmitoyltransferase-1 (CPT1), thereby facilitating mitochondrial FAO. Inhibiting MLYCD is expected to elevate malonyl-CoA levels, suppress FAO, and induce apoptosis driven by metabolic stress. Based on this, we hypothesized that inhibiting FAO by suppressing malonyl-CoA decarboxylase (MLYCD) would disrupt GBM metabolic homeostasis and reduce tumour cell survival. To evaluate this therapeutic target, we performed siRNA-mediated knockdown of MLYCD in the human glioma cell line SW1088. Transfection achieved 95% reduction of MLYCD transcript levels as confirmed by RT-qPCR. Loss of MLYCD expression resulted in a significant reduction in cell viability and robust induction of cell death, demonstrating that MLYCD is essential for glioma cell survival. Additionally, we tested our preliminary study using a novel small-molecule MLYCD covalent inhibitor (MCD-18STA-18) in SW1088 cells, demonstrating a significant dose-dependent reduction in cell viability. The defined IC50 for this pharmacological inhibition, established by tetrazolium-based viability assay (MTS), further supports MLYCD as a promising target for metabolic vulnerability in human glioma cells. Building on these findings, future studies will elucidate the metabolic effect of MLYCD inhibition by quantifying glucose and palmitate oxidation and mitochondrial function using Seahorse metabolic flux analyses. Targeted metabolomics will measure malonyl-CoA, acetyl-CoA, and acyl-carnitine profiles to confirm suppression of fatty acid oxidation. Mechanistic assays evaluating apoptosis, mitochondrial dysfunction, and changes in cell invasion and migration will further characterize the downstream effects of MLYCD inhibition. Finally, the therapeutic relevance of this approach will be tested in vivo using a human glioblastoma xenograft model, including pharmacodynamic analysis of FAO inhibition and tumour response. Together, these future studies will provide a comprehensive evaluation of MLYCD inhibition as a metabolic target in glioblastoma and support its potential as a novel therapeutic strategy. Citation Format: Nowreen Islam Chowdhury, Syed Tareq, Heba Ewida, Mahmoud Ahmed, Heidi Villalba. Metabolic reprogramming in glioma: Targeting fatty acid oxidation via malonyl-CoA decarboxylase (MLYCD) inhibition abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr B049.