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

## TL;DR

A new long noncoding RNA, Wee1-AS, helps regulate fatty acid metabolism in the liver and may offer a new treatment for liver disease.

## Contribution

Wee1-AS is a novel lncRNA that regulates mitochondrial fatty acid oxidation through CDK1/CYCLIN B1 activation and interacts with WEE1 inhibition.

## Key findings

- Wee1-AS overexpression in mice reduced MASLD symptoms and improved liver function.
- Wee1-AS activates mitochondrial fatty acid oxidation by stabilizing CYCLIN B1 and suppressing Wee1 transcription.
- The human homolog LNC106435.1 also improves mitochondrial function, suggesting therapeutic potential for MASLD.

## 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.