LncRNA Wee1-AS coordinates oxidative fatty acid metabolism through the activation of mitochondrial CDK1/CYCLIN B1

  • Signal Transduct Target Ther. 2026 Jan 10;11(1):13. doi: 10.1038/s41392-025-02558-4.
Hyeon-Ji Kim  #  1  2 ,  Cheolhee Jeong  #  1 ,  Sang-Heon Lee  1 ,  Seungchan An  1  2 ,  Gyu Hwan Hyun  1  2 ,  Ga Young Lim  1 ,  Ju-Yeon Kim  1 ,  Junhyeong Lee  3  4 ,  Min-Jung Park  3 ,  Sung Won Kwon  1  2 ,  Won Kim  5 ,  Minsoo Noh  1  2 ,  Yong-Hyun Han  6 ,  Mi-Ock Lee  7  8  9
Affiliations
  • 1. College of Pharmacy, Seoul National University, Seoul, Korea.
  • 2. Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
  • 3. Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
  • 4. College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju, Korea.
  • 5. Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
  • 6. Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
  • 7. College of Pharmacy, Seoul National University, Seoul, Korea. [email protected].
  • 8. Bio-MAX Institute, Seoul National University, Seoul, Korea. [email protected].
  • 9. Natural Product Research Institute, Seoul National University, Seoul, Korea. [email protected].
  • # Contributed equally.
PMID: 41519884 DOI: 10.1038/s41392-025-02558-4
Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is steadily increasing with life-threatening complications, underscoring the need for new therapeutic targets. In this study, we identified a novel long noncoding RNA, Wee1-AS, which is transcribed from the antisense strand of the Wee1 gene locus. The expression of Wee1-AS was greater in hepatocytes, particularly in the region around the central vein, and it was induced in response to high-fat diet challenge. Adeno-associated virus-mediated overexpression of Wee1-AS in mice strongly suppressed the symptoms of MASLD, underscoring its pivotal roles. Mechanistically, Wee1-AS enhances mitochondrial fatty acid oxidation by activating the CDK1/CYCLIN B1 complex through two mechanisms. First, it suppressed the transcription of the Wee1 gene by preventing access to the transcriptional machinery. Second, Wee1-AS bound and stabilized the CYCLIN B1 protein by suppressing ubiquitin/proteasome-mediated degradation. Notably, treatment with the Wee1 Inhibitor adavosertib ameliorated MASLD symptoms by improving mitochondrial function in the liver. Consistently, knockdown of Wee1-AS led to lipid accumulation and mitochondrial dysfunction, both of which were reversed by adavosertib treatment in hepatocytes, indicating a functional interplay between Wee1-AS and Wee1 in regulating fatty acid oxidation. Furthermore, we identified a human homolog, LNC106435.1, which improved mitochondrial function, suggesting that the modulation of LNC106435.1 may have potential therapeutic implications for managing MASLD.

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