SIRT1-mediated deacetylation of Lysyl-tRNA synthetase reprograms lipid metabolism to promote colorectal tumorigenesis

Abstract Aminoacyl-tRNA synthetases (AARSs) have long been recognized for their canonical role in protein synthesis, catalyzing the attachment of amino acids to their cognate tRNAs. However, accumulating evidence has revealed that many AARSs also exert non-canonical functions under various physiological and pathological conditions. Despite this, the specific contributions of AARSs to tumorigenesis remain poorly understood. In this study, we demonstrated that lysyl-tRNA synthetase (LysRS), a key member of the AARS family, is significantly overexpressed in colorectal cancer (CRC) and associated with poor prognosis. Mechanistically, LysRS undergoes reversible acetylation at K175 and K249, which regulates its ubiquitination and stability. Specifically, PCAF-mediated acetylation promotes LysRS ubiquitination and degradation, whereas SIRT1-mediated deacetylation, particularly under glucose starvation, enhances LysRS stability and increases its nuclear accumulation. Within the nucleus, LysRS physically interacts with the transcriptional coactivator PGC-1β and drives the expression of fatty acid oxidation (FAO)-related genes, including MCAD , LCAD , and CPT1A , thereby enabling metabolic adaptation to nutrient stress. Functionally, a deacetylation-mimetic LysRS mutant (2KR) enhances FAO activity, suppresses lipid droplet accumulation, and accelerates tumor growth in vivo. Importantly, pharmacological blockade of FAO largely abolished the tumor-promoting effect of the 2KR mutant in a xenograft model. Collectively, our findings uncover a previously unrecognized SIRT1–LysRS–PGC-1β axis that drives CRC progression through metabolic reprogramming, and highlight LysRS acetylation as a potential prognostic biomarker and therapeutic target in CRC.