Targeting leucyl-tRNA synthetase 1 with leucine restores N-glycosylation and overcomes chemoresistance in ICC

Selective mRNA translation enables tumour cells to redistribute resources and withstand chemical stress, but the underlying mechanisms remain poorly understood. Here, we demonstrate that leucyl-tRNA synthetase 1 (LARS1) is significantly decreased in ICC and correlates with poor prognosis.

Using overexpression and knockout mouse models, we establish the crucial role of LARS1 in ICC chemoresistance. Mechanistically, LARS1 knockdown selectively suppresses the mRNA translation of N-glycan biosynthesis enzymes in a leucine codon frequency-dependent manner, reducing the N-glycosylation of ABCC1 at the N929 site and promoting ICC chemoresistance. Notably, exogenous leucine supplementation emerges effectively restore LARS1 expression and enhance chemotherapy efficacy in ICC.