The mA methyltransferase Mettl3 deficiency attenuates hepatic stellate cell activation and liver fibrosis.

Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (mA) is the most abundant internal RNA modification in eukaryotic cells and is dynamically regulated under various physiological and pathophysiological conditions. However, the functional role of Mettl3-mediated mA in liver fibrosis remains elusive. Here, we found that the HSC-specific knockout of mA methyltransferase Mettl3 suppressed HSC activation and significantly alleviated liver fibrosis. Multi-omics analysis of HSCs showed that Mettl3 depletion reduced mA deposition on mRNA transcripts of Lats2 (a central player of the Hippo/YAP signaling pathway) and slowed down their degradation. Elevated Lats2 increased phosphorylation of the downstream transcription factor YAP, suppressed YAP nuclear translocation, and decreased pro-fibrotic gene expression. Overexpressing YAP mutant resistant to phosphorylation by Lats2 partially rescued the activation and pro-fibrotic gene expression of Mettl3-deficient HSCs. Our study revealed that disruption of Mettl3 in HSCs mitigated liver fibrosis by controlling the Hippo/YAP signaling pathway, providing potential therapeutic strategies to alleviate liver fibrosis by targeting epitranscriptomic machinery.