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

  • Nat Commun. 2025 Jul 30;16(1):6996. doi: 10.1038/s41467-025-62148-4.
Sunyoung Seo  #  1 ,  Min Ji Park  #  1 ,  Min Gi Park  #  1 ,  Minseo Gwak  1 ,  Yoonji Kim  1 ,  Junseok Jang  1 ,  Nayoung Hong  1 ,  Bok-Sim Lee  2 ,  Chohee Kim  2 ,  Seonguk Jo  1 ,  Hyun Bo Shim  1 ,  Hyun-Jin Kim  3 ,  Myung Hun Kim  4 ,  Seo Hyun Yoo  1 ,  Seunghyun Yoon  1 ,  Sua Kim  1 ,  Jae Hyuk Lee  1 ,  Sang-Hun Choi  1 ,  Seon Yong Lee  1 ,  Gyu-Bum Yeon  1 ,  Sung-Hye Park  5 ,  Sung-Hak Kim  3 ,  Hyunjeong Lee  1  6 ,  Joo-Yong Lee  4 ,  Dae-Sung Kim  1 ,  Byung Cheon Lee  1 ,  Jong-Whi Park  7 ,  Hyunggee Kim  8
Affiliations
  • 1. Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
  • 2. Department of Life Sciences, Gachon University, Incheon, 21999, Republic of Korea.
  • 3. Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • 4. Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, 34133, Republic of Korea.
  • 5. Department of Pathology, Seoul National University Hospital, Seoul, 03082, Republic of Korea.
  • 6. College of Engineering, Institute of Green Manufacturing Research Center, Korea University, Seoul, 02841, Republic of Korea.
  • 7. Department of Life Sciences, Gachon University, Incheon, 21999, Republic of Korea. [email protected].
  • 8. Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, 02841, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 40739132 DOI: 10.1038/s41467-025-62148-4
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.

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