Lactic acid promotes metastasis of papillary thyroid carcinoma by enhancing CPT1A lactylation

Papillary thyroid carcinoma (PTC), the most prevalent thyroid malignancy, exhibits aggressive behavior in subsets with metastasis. Despite advances in risk stratification, biomarkers predicting metastatic potential remain limited. Here, we identify lactate as a critical driver of PTC metastasis through lactylation of carnitine palmitoyltransferase 1 A (CPT1A), the rate-limiting enzyme in fatty acid β-oxidation (FAO). Multi-omics profiling of 27 paired PTC tissues revealed elevated lactate levels and FAO activation, corroborated by TCGA data. Functional assays demonstrated that exogenous lactate enhances PTC cell migration via CPT1A-dependent FAO. Mechanistically, lactate upregulated CPT1A transcription by promoting histone H3K18 lactylation (H3K18la), simultaneously stabilized CPT1A protein via lactylation of CPT1A at K180/K285 to suppress its ubiquitin-proteasomal degradation. Genetic or pharmacological inhibition of CPT1A abolished lactate-driven migration and FAO activity. In vivo, lactylation-deficient CPT1A mutants (K180R/K285R) attenuated lung metastasis and subcutaneous tumor growth in nude mice. This study reveals that lactate-CPT1A axis synergistically amplifies FAO to fuel PTC progression, suggesting CPT1A lactylation as a therapeutic vulnerability for metabolic intervention.