METTL1‐Mediated M ⁷ G tRNA Modification Promotes Residual Liver Regeneration After Hepatectomy via Translational Control

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.