Metabolic traits shape responses to LSD1-directed therapy in glioblastoma tumor-initiating cells.

Lysine-specific histone demethylase 1A (LSD1) is an epigenetic regulator involved in various biological processes, including metabolic pathways. We demonstrated the therapeutic potential of its pharmacological inhibition in glioblastoma using DDP_38003 (LSD1i), which selectively targets tumor-initiating cells (TICs) by hampering their adaptability to stress. Through biological, metabolic, and omic approaches, we now show that LSD1i acts as an endoplasmic reticulum (ER) stressor, activating the integrated stress response and altering mitochondrial structure and function. These effects impair TICs' oxidative metabolism and generate reactive oxygen species, further amplifying cellular stress. LSD1i also impairs TICs' glycolytic activity, causing their metabolic decline. TICs with enhanced glycolysis benefit from LSD1-directed therapy. Conversely, metabolically silent TICs mantain ER and mitochondrial homeostasis, adapting to stress conditions, including LSD1i treatment. A dropout short hairpin RNA screening identifies postglycosylphosphatidylinositol attachment to proteins inositol deacylase 1 (PGAP1) as a mediator of resistance to LSD1i. Disruptions in ER and mitochondrial balance holds promise for improving LSD1-targeted therapy efficacy and overcoming treatment resistance.