Article
Restoration of N-glycosylation via leucine-activated leucyl-tRNA synthetase 1 overcomes chemoresistance in intrahepatic cholangiocarcinoma
Published in
Journal of Hepatology
Abstract
This study demonstrated that leucyl-tRNA synthetase 1 (LARS1), a key enzyme in tRNA charging, regulates chemotherapy response in intrahepatic cholangiocarcinoma (ICC). Loss of LARS1 impaired leucyl-tRNA charging, selectively reducing translation of leucine codon–enriched transcripts involved in N-glycosylation, thereby promoting chemoresistance. Leucine supplementation restored LARS1 activity and improved chemosensitivity, highlighting tRNA charging as a critical regulatory layer linking amino acid metabolism, translation, and cancer therapy.
Results
• Chemotherapy promoted ubiquitin-mediated degradation of LARS1, decreasing charged leucyl-tRNA levels.
• Impaired leucyl-tRNA charging selectively reduced translation of leucine codon–enriched transcripts and promoted chemoresistance.
• Reduced tRNA charging impaired translation of key N-glycosylation enzymes (ALG3, RFT1, ALG12), leading to decreased N-glycosylation.
• Loss of ABCC1 glycosylation enhanced drug efflux activity and reduced chemotherapy sensitivity (Fig. 1).
• Exogenous leucine restored LARS1-dependent tRNA charging and synergized with chemotherapy in vivo.
Fig. 1. LARS1-mediated tRNA charging regulates codon-biased translation, N-glycosylation, and chemoresistance.
Conclusion
This study highlights that tRNA charging is not merely a housekeeping process for protein synthesis but a key regulatory mechanism in cancer biology. LARS1-mediated leucyl-tRNA charging controls codon-biased translation and downstream glycosylation pathways that determine chemotherapy response. These findings underscore the importance of studying tRNA charging as an emerging regulatory layer in cancer progression and therapeutic resistance.
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