The loss of aars1 in zebrafish increases tolerance to hypoxia by reducing hif1α degradation via the autophagy-lysosome pathway.

Alanyl-tRNA synthetase 1 (AARS1) has been identified as an enzyme that can recognise L-lactate directly and function as a lactyltransferase. However, its potential regulatory role in hypoxia tolerance remains unclear. In this study, we generated aars1 mutants in zebrafish using the CRISPR/Cas9 technique. We found that homozygous loss of aars1 was lethal, whereas heterozygous loss significantly enhanced hypoxia tolerance. Further investigation revealed that AARS1 negatively regulates HIF1α-mediated hypoxia signaling by promoting HIF1α degradation. Loss of AARS1 enhanced HIF1α stability and hypoxia-responsive gene expression; however, AARS1 restoration reversed this effect. This regulation mainly depended on the autophagy-lysosome pathway, revealing a non-canonical role for AARS1 in modulating HIF1α stability and adaptation to hypoxia.