Article
Restoration of N-glycosylation via leucine-activated leucyl-tRNA synthetase 1 overcomes chemoresistance in intrahepatic cholangiocarcinoma
Published in
Journal of Hepatology
Abstract
How chemotherapy sensitivity is controlled in intrahepatic cholangiocarcinoma (iCCA) is not fully understood. This paper identifies leucyl-tRNA synthetase 1 (LARS1), an essential component of the tRNA charging apparatus, as a decisive factor in drug response. In advanced tumors LARS1 levels are low, and this reduction tracks with unfavorable patient outcomes. When LARS1 is lost, leucyl-tRNA charging declines and, through codon-biased translational control, the production of N-glycan biosynthesis enzymes drops selectively. The resulting under-glycosylation of the drug transporter ABCC1 strengthens drug efflux and drives chemoresistance. Notably, leucine supplementation rescues LARS1 activity, restores N-glycosylation, and boosts the efficacy of chemotherapy.
Results
• LARS1 is markedly reduced in iCCA and its levels correlate positively with patient survival.
• LARS1 loss triggers chemoresistance in cultured cells and in mouse models.
• Weakened LARS1 activity lowers leucyl-tRNA charging and preferentially suppresses translation of the N-glycosylation enzymes ALG3, RFT1, and ALG12.
• Impaired N-glycosylation leaves the multidrug transporter ABCC1 hypoglycosylated, increasing drug efflux.
• Leucine supplementation restores LARS1 expression, repairs N-glycan biosynthesis, and strengthens gemcitabine-oxaliplatin treatment.
Fig. 1. LARS1-dependent tRNA charging controls N-glycosylation and chemotherapy responsiveness.
Conclusion
The results establish tRNA charging by LARS1 as a central determinant of selective translation and N-glycosylation pathways that set chemotherapy sensitivity in iCCA. Reduced LARS1 activity drives resistance through translational defects that compromise glycosylation of key transport proteins. The work places tRNA charging at the center of cancer drug response and raises the possibility that leucine supplementation could be used to combat chemotherapy resistance.
tRNA Charging Sequencing
Arraystar tRNA Charging Seq (modification-induced misincorporation tRNA-seq) delivers simultaneous tRNA expression, modification, and charging profiles in a single experiment. The service supports tRNA studies in cancer drug resistance, cardiac fibrosis, and many other disease areas.
Advantages
• One assay, three profiles: tRNA expression, tRNA modification, and tRNA charging.
• Full-length tRNA enrichment: high-efficiency full-length cDNA synthesis reduces mapping and counting inaccuracy.
• Broad modification coverage: m1A, m1G, m3C, acp3U and more predicted at single-nucleotide resolution.
• Translatomics-ready: correlates tRNA charging with translational activity.
• Rich outputs: multi-omics data with differential analyses and detailed annotations.
• Publication-ready graphics and visualization.