DHRS13 suppresses differentiation and mitophagy in glioma via retinoic acid and mitochondrial reactive oxygen species

Sunyoung Seo, Min Ji Park, Min Gi Park, Minseo Gwak, Yoonji Kim, Junseok Jang, Nayoung Hong, Bok-Sim Lee, Chohee Kim, Seonguk Jo, Hyun Bo Shim, Hyun-Jin Kim, Myung Hun Kim, Seo Hyun Yoo, Seunghyun Yoon, Sua Kim, Jae Hyuk Lee, Sang-Hun Choi, Seon Yong Lee, Gyu-Bum Yeon, Sung-Hye Park, Sung-Hak Kim, Hyunjeong Lee, Joo-Yong Lee, Dae-Sung Kim, Byung Cheon Lee, Jong-Whi Park () and Hyunggee Kim ()
Additional contact information
Sunyoung Seo: Korea University
Min Ji Park: Korea University
Min Gi Park: Korea University
Minseo Gwak: Korea University
Yoonji Kim: Korea University
Junseok Jang: Korea University
Nayoung Hong: Korea University
Bok-Sim Lee: Gachon University
Chohee Kim: Gachon University
Seonguk Jo: Korea University
Hyun Bo Shim: Korea University
Hyun-Jin Kim: Chonnam National University
Myung Hun Kim: Chungnam National University
Seo Hyun Yoo: Korea University
Seunghyun Yoon: Korea University
Sua Kim: Korea University
Jae Hyuk Lee: Korea University
Sang-Hun Choi: Korea University
Seon Yong Lee: Korea University
Gyu-Bum Yeon: Korea University
Sung-Hye Park: Seoul National University Hospital
Sung-Hak Kim: Chonnam National University
Hyunjeong Lee: Korea University
Joo-Yong Lee: Chungnam National University
Dae-Sung Kim: Korea University
Byung Cheon Lee: Korea University
Jong-Whi Park: Gachon University
Hyunggee Kim: Korea University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract To elucidate the complex interplay of undifferentiated cancer cells in malignancy, we focus on the crucial mechanisms that maintain the undifferentiated state of cancer stem-like cells, which drive tumor growth and therapy resistance. Here, we identify a protein called dehydrogenase/reductase 13 (DHRS13) that is 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 high affinity for NADPH. Mechanistically, DHRS13 prevents glioma stem-like cells from differentiating by blocking retinoic acid signaling, thereby maintaining their undifferentiated state. Remarkably, the depletion of DHRS13 results in mitochondrial reactive oxygen species-driven mitophagy and cell death. Consequently, loss of DHRS13 leads to a significant decrease in tumor initiation and progression. These findings hold promise for the development of strategies that target undifferentiated cancer cells, potentially leading to improved treatment outcomes.

Date: 2025
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DOI: 10.1038/s41467-025-62148-4

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