Comprehensive pan-cancer analysis of AARS1, a newly identified lactyltransferase in human cancers.

Alanyl-tRNA Synthetase 1 (AARS1) is a bifunctional enzyme with emerging roles in lactate sensing and protein lactylation (Kla), both driving tumor progression. However, its clinical significance across diverse cancer types remains largely unexplored. Leveraging comprehensive bioinformatics analysis across multiple public repositories, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Tumor IMmune Estimation Resource (TIMER), The University of Alabama at Birmingham CANcer data analysis Portal (UALCAN), and Human Protein Atlas (HPA), we systematically evaluated AARS1 expression and its associations with TP53 mutations, DNA methylation, prognostic outcomes, and genetic alterations, as well as its correlation with the immune microenvironment. Functional enrichment analyses were further conducted to elucidate its molecular mechanisms. Moreover, immunohistochemistry (IHC) in renal and lung cancers, complemented by in vitro functional assays in renal cancer cells, validated its oncogenic role. Our results demonstrate that AARS1 is significantly upregulated in most malignancies and correlates with poor survival rates. Notably, AARS1 exhibited high diagnostic efficacy (AUC > 0.85) and was inversely associated with antitumor immune infiltration. Functional downregulation of AARS1 significantly inhibited the proliferation, migration, and invasion abilities of these cells, whereas overexpression of the enzymatically inactive mutant failed to rescue these inhibitory effects, further confirming that its pro-tumorigenic role is dependent on its lactyltransferase activity. This inaugural pan-cancer study highlights AARS1 as a robust diagnostic and prognostic biomarker, immunological indicator, and promising therapeutic target across multiple cancers.