STEM-02. MODULATING INTRACELLULAR RETINOIC ACID METABOLISM TO TARGET GLIOMA STEM CELLS

Abstract To elucidate how undifferentiated cancer cells contribute to tumor aggressiveness and treatment failure, we investigated key regulators that preserve the stem-like state in glioblastoma. We identified dehydrogenase/reductase 13 (DHRS13) as a mitochondria-localized enzyme that is highly enriched in undifferentiated glioblastoma cells. DHRS13 efficiently catalyzes the NADPH-dependent reduction of all-trans-retinaldehyde to all-trans-retinol. Mechanistically, DHRS13 prevents the accumulation of intracellular retinoic acid (RA), thereby suppressing differentiation and maintaining the stem-like state of glioma cells. DHRS13 depletion triggers RA-mediated mitochondrial oxidative stress, leading to mitophagy and subsequent cell death. Importantly, silencing of DHRS13 markedly delays tumor progression and improves survival in orthotopic glioma models. Our findings identify DHRS13 as a potential therapeutic target to eliminate undifferentiated glioblastoma cells and enhance treatment efficacy.