LncRNA WEE1-AS coordinates oxidative fatty acid metabolism through the activation of mitochondrial Cdk1/Cyclin B1

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent with life-threatening complications, underscoring the need for new therapeutic targets. In this study, we identified a novel long non-coding RNA (lncRNA), WEE1-AS, which is transcribed from the antisense strand of the Wee1 gene locus. Hepatic WEE1-AS was expressed in a spatiotemporal manner in response to a high-fat diet challenge. Functionally, WEE1-AS enhanced 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. Furthermore, we identified a human homolog, lnc106435.1, which improved mitochondrial function, suggesting that targeting lnc106435.1 could be a valuable therapeutic strategy for managing MASLD. Overall design: to investigate the function of lnc RNA Wee1-AS in the regulation of cell cyle and metabolic process in the C57BL/6 mice liver, we overexpressed the Wee1-AS in the liver by injecting AAV-Wee1-AS through retro-orbital injection to high-fat diet fed mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 liver samples at one time points. comparative gene expression profiling analysis of RNA-seq data for mouse liver samples (HFD with AAV-GFP, HFD with AAV-Wee1-AS)