Wnt Signalling‐Activated <scp>EN2</scp> Promotes the Progression of Glioblastoma by Upregulating Fatty Acid Synthesis Metabolism

Glioblastoma (GBM) is the most aggressive primary brain tumour, with limited treatment options and a propensity for rapid development of resistance to therapies. Previous studies have indicated that fatty acid metabolic reprogramming is a critical marker of tumour progression and plays a significant role in the proliferation and migration of cancer cells. However, research on fatty acid synthesis metabolism in GBM is relatively limited, and the underlying mechanisms warrant further investigation. In this study, we identified a significant correlation between the expression of Engrailed 2 (EN2) and poor prognosis in GBM patients. Both in vivo and in vitro experiments demonstrated that EN2 promotes GBM progression and facilitates fatty acid metabolic reprogramming. Mechanistically, EN2 activates the expression of Sterol Regulatory Element-Binding Protein 1 (SREBP1), thereby enhancing the fatty acid synthesis metabolic pathway and contributing to tumour resistance. Furthermore, we found that EN2 is primarily regulated by the Wnt signalling pathway and T-cell factor 4 (TCF4). Targeting EN2 enhances the efficacy of chemotherapy in GBM and prolongs survival in mouse models. Overall, our findings suggest that EN2 represents a potential therapeutic target for GBM and underscores its role in promoting fatty acid synthesis metabolism in GBM cells.