Lysine-specific histone demethylase 1A (LSD1) is an epigenetic regulator involved in several biological processes, including metabolic pathways. We established the therapeutic benefit of its pharmacological inhibition in glioblastoma (GBM) using DDP_38003 (LSD1i), which selectively targets tumor-initiating cells (TICs) by hampering their adaptability to stress. Here, we demonstrate that LSD1i is a stress-inducing agent activating the integrated stress response by itself and triggering rearrangements of mitochondria which impact TICs oxidative metabolism.