# METTL1‐Mediated M7G tRNA Modification Promotes Residual Liver Regeneration After Hepatectomy via Translational Control

## TL;DR

This study shows that METTL1 helps the liver regenerate after surgery by modifying tRNA, which boosts the production of key proteins involved in liver recovery.

## Contribution

The study identifies METTL1-mediated m7G tRNA modification as a novel regulator of liver regeneration through translational control of Hippo pathway effectors.

## Key findings

- METTL1 is significantly upregulated after partial hepatectomy and correlates with better clinical outcomes.
- METTL1 enhances liver regeneration by improving hepatocyte proliferation and translational efficiency of Hippo pathway genes YAP/TAZ.
- Modulating the METTL1-YAP/TAZ axis promotes liver recovery after surgery.

## Abstract

Partial hepatectomy (PHx) has emerged as a primary therapeutic intervention for end‐stage liver pathologies. However, post‐hepatectomy liver failure (PHLF), a critical complication arising from inadequate regenerative capacity of the remnant liver, underscores the clinical imperative to understand molecular mechanisms governing hepatic regeneration. Through an integrative multi‐omics analysis in a murine 70% PHx model coupled with clinical correlation studies, the tRNA m7G methyltransferase METTL1 was identified as a pivotal regulator of post‐resection hepatic recovery. METTL1 exhibited significant temporal upregulation following PHx, with its expression profile positively correlating with favorable clinical outcomes in surgical patients. Genetic ablation of METTL1 substantially attenuated hepatocyte proliferation and compromised regenerative capacity, whereas its ectopic expression potentiated liver regeneration through enhanced translational efficiency. Mechanistic investigations revealed that METTL1‐mediated m7G tRNA modification orchestrates regenerative processes by selectively augmenting the translation of Hippo pathway effectors YAP/TAZ. Most importantly, modulation of the METTL1‐YAP/TAZ signaling axis successfully promotes liver regeneration after PHx. This study elucidates a previously unrecognized translational control mechanism underlying liver regeneration, proposing METTL1 as a promising molecular target for preventing PHLF through therapeutic enhancement of hepatic regenerative potential.

METTL1 and its mediated m7G tRNA modification are significantly up‐regulated after partial hepatectomy (PHx). Overexpression of METTL1 improves the efficiency of liver regeneration after PHx, increases the proliferation of hepatocytes, and accelerates the recovery of liver function. METTL1‐mediated m7G tRNA modification selectively governs the translation efficiency of the Hippo signaling pathway genes.