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<p>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, <i>Wee1-AS</i>, which is transcribed from the antisense strand of the <i>Wee1</i> gene locus. The expression of <i>Wee1-AS</i> 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 <i>Wee1-AS</i> in mice strongly suppressed the symptoms of MASLD, underscoring its pivotal roles. Mechanistically, <i>Wee1-AS</i> enhances mitochondrial fatty acid oxidation by activating the CDK1/CYCLIN B1 complex through two mechanisms. First, it suppressed the transcription of the <i>Wee1</i> gene by preventing access to the transcriptional machinery. Second, <i>Wee1-AS</i> 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 <i>Wee1-AS</i> led to lipid accumulation and mitochondrial dysfunction, both of which were reversed by adavosertib treatment in hepatocytes, indicating a functional interplay between <i>Wee1-AS</i> and WEE1 in regulating fatty acid oxidation. Furthermore, we identified a human homolog, <i>LNC106435.1</i>, which improved mitochondrial function, suggesting that the modulation of <i>LNC106435.1</i> may have potential therapeutic implications for managing MASLD.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月10日

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  • Hyeon-Ji Kim,
  • Cheolhee Jeong,
  • Sang-Heon Lee,
  • Seungchan An,
  • Gyu Hwan Hyun,
  • Ga Young Lim,
  • Ju-Yeon Kim,
  • Junhyeong Lee,
  • Min-Jung Park,
  • Sung Won Kwon,
  • Won Kim,
  • Minsoo Noh,
  • Yong-Hyun Han,
  • Mi-Ock Lee

摘要

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.