This study investigated the role of alanyl-tRNA synthetase 1 (AARS1) as a protein lactyltransferase in hepatocellular carcinoma (HCC), examining how it links glycolysis to immune evasion via ATF6 lactylation and tryptophan metabolism, using single-cell/spatial transcriptomics, murine hepatocyte-specific knockout models, and human PET/CT data.
AARS1 lactylates ATF6 at lysine 424, stabilizing it and driving TDO2-mediated L-kynurenine production, which promotes regulatory T cell (Treg) expansion; a Treg-derived eNAMPT feedback loop reinforces this cycle. Hepatocyte-specific AARS1 knockout suppressed tumor growth and reduced Treg abundance in murine models. Pharmacological inhibition with β-alanine sensitized tumors to PD-1/PD-L1 blockade.
Findings from murine hepatocyte-specific knockout models may not fully translate to human HCC biology. The study is primarily mechanistic; no clinical trial data on β-alanine or combination immunotherapy efficacy in patients is provided. The PET/CT correlation is observational and does not establish causality between glycolytic flux and AARS1 activity in patients.
AARS1 inhibition with β-alanine represents a potential strategy to overcome immunotherapy resistance in HCC by breaking a glycolysis-lactylation-Treg feedback loop. Clinicians should watch for early-phase trials combining AARS1 inhibitors with PD-1/PD-L1 blockade in HCC.
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