Lysine-specific demethylase 1 links metabolism to stemness in human neural stem cells.

Epigenetic regulation of stem cell fate requires tight coordination with cellular metabolism; however, key downstream effectors remain poorly defined. Here, we show that lysine-specific demethylase 1 (LSD1) governs metabolic programs essential for stemness in human fetal neural stem cells. LSD1 inhibition induced a pronounced glycolytic shift accompanied by altered lineage commitment, characterized by suppression of neuronal differentiation and promotion of astrocytic fate. Machine learning-based Elastic Net analysis of transcriptomic data identified a subset of metabolic genes, including PLPP2 and CPT1A, which regulate phospholipid metabolism and mitochondrial fatty acid oxidation, as key downstream effectors of LSD1. Functional perturbation experiments showed that knockdown of these candidates attenuated LSD1 inhibition-induced glycolytic activation and ameliorated distinct differentiation phenotypes. Chromatin immunoprecipitation sequencing revealed LSD1 occupancy at metabolic gene loci, supporting their transcriptional repression by LSD1. Together, these findings identify LSD1 as an epigenetic gatekeeper preserving stemness by restraining glycolysis and inappropriate lineage commitment.