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August 16, 2026European Respiratory Journal

YY1 lactylation mediates epithelial barrier dysfunction during acute lung injury

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Authors

NLNing LiYLYi LiuMGMinglang Gao

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Overview

Preclinical study demonstrates that lactate-driven YY1 lactylation disrupts epithelial barriers in acute lung injury, highlighting a therapeutic target for ARDS.

Key Points

  • To elucidate the functional role and molecular mechanism of lactate accumulation and protein lactylation in alveolar epithelial barrier breakdown during acute lung injury.
  • Quantified lactate levels in clinical ARDS patient samples and experimental ALI mouse models.
  • Modulated lactate production using glycolysis inhibitor 2-DG, exogenous lactate, and pulmonary LDHA knockdown (AAV9-shLdha).
  • Characterized Tip60-dependent YY1 K183 lactylation, downstream PGC-1α transcriptional repression, and therapeutic interventions using a YY1-K183R mutant, a targeted cell-penetrating peptide, and glycyrrhizin.
  • Lactate accumulation promoted Tip60-mediated YY1 K183 lactylation, which transcriptionally repressed PGC-1α, impaired mitochondrial homeostasis, and destroyed alveolar epithelial barrier integrity.
  • Genetic ablation of pulmonary LDHA or expression of lactylation-deficient YY1-K183R protected mice from LPS-induced acute lung injury.
  • Therapeutic treatment with a K183-targeted cell-penetrating peptide or glycyrrhizin suppressed YY1 lactylation, restored PGC-1α and mitochondrial function, and alleviated pulmonary edema and inflammation.

Cite This Study

Li et al. (2026) studied this question.

synapsesocial.com/papers/6a8179bcf2fb91fc834ad0bahttps://doi.org/10.1183/13993003.02717-2025
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