AARS1 promotes tumor progression and immune evasion via ATF6 lactylation-mediated tryptophan metabolism in hepatocellular carcinoma.
basic_science · Level V
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- Record sourced from PubMed, PMID 42379172.
- Also identified by DOI 10.1016/j.cmet.2026.06.003.
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Abstract
Glycolysis and protein lactylation both drive hepatocellular carcinoma (HCC) progression, yet their mechanistic interplay remains unclear. Through integrated single-cell and spatial transcriptomic analyses stratified by glycolytic activity, we identified alanyl-tRNA synthetase 1 (AARS1), a recently characterized protein lactyltransferase, as a key metabolic-immune regulator in HCC. Clinically, AARS1 is upregulated in tumors, correlates with elevated glycolytic flux measured by <sup>18</sup>F-fluorodeoxyglucose (<sup>18</sup>F-FDG) positron emission tomography/computed tomography (PET/CT), poor prognosis, and immunotherapy resistance. In murine models, hepatocyte-specific knockout of AARS1 suppressed tumor growth and reduced the abundance of regulatory T cells (Tregs). Mechanistically, AARS1 catalyzes the lactylation of activating transcription factor 6 (ATF6) at lysine 424, preventing its degradation and leading to transcriptional activation of TDO2. This process promotes L-kynurenine production and supports Treg differentiation and function. Furthermore, L-kynurenine-AHR signaling drives eNAMPT secretion from Tregs, which augments tumor cell glycolysis and lactate production, thereby reinforcing a feedback loop that sustains AARS1-catalyzed ATF6 lactylation. Pharmacological inhibition of AARS1 with β-alanine sensitized tumors to PD-1/PD-L1 blockade.