The short-chain dehydrogenases/reductase DHRS13 suppresses differentiation and mitophagy in glioma cells by modulating retinoic acid signaling and mitochondrial ROS

To better understand the complex interplay of undifferentiated cancer cells in tumor malignancy, we have focused on the crucial mechanisms that maintain the undifferentiated state of cancer stem-like cells, which drive tumor growth and therapy resistance. Here, we have identified a protein called dehydrogenase/reductase 13 (DHRS13) abundant in undifferentiated glioblastoma cells. DHRS13 is primarily located in the mitochondria and functions as a retinaldehyde reductase, converting all-trans retinaldehyde to all-trans retinol with a high affinity for NADPH. Remarkably when we deplete DHRS13 from these cells, we observe a significant decrease in tumor initiation and progression. Mechanistically, DHRS13 prevents these cells from differentiating by blocking retinoic acid signaling, thereby maintaining their undifferentiated state. Additionally, depletion of DHRS13 results in mitochondrial reactive oxygen species-driven mitophagy and cell death. These findings hold promise for the development of novel strategies to target undifferentiated cancer cells and potentially leading to improved treatment outcomes.