YY1 lactylation mediates epithelial barrier dysfunction during acute lung injury

Area of Science:

• Biochemistry
• Cell Biology
• Pathophysiology

Background:

• Elevated lactate in lung tissue is a hallmark of acute lung injury (ALI).
• The role of lactate and its modifications in damaged alveolar epithelial cells is not well understood.
• Acute respiratory distress syndrome (ARDS) is a severe form of ALI with high mortality.

Purpose of the Study:

• To elucidate the biological functions of lactate accumulation and lactylation in ALI.
• To investigate the mechanism linking lactate to alveolar epithelial barrier dysfunction.
• To identify potential therapeutic targets for ALI and ARDS.

Main Methods:

• Validation of increased lactate in ALI/ARDS patient samples and mouse models.
• Administration of glycolysis inhibitor 2-DG and exogenous lactate.
• Genetic silencing of LDHA using AAV9-shLdha.
• Biochemical assays to detect YY1 lactylation at K183.
• In vivo rescue experiments with lactylation-deficient YY1-K183R mutant.
• Screening of therapeutic candidates targeting YY1 lactylation.

Main Results:

• Lactate depletion mitigated ALI, while lactate supplementation worsened it.
• Lactate accumulation promoted YY1 lactylation at K183, inhibiting PGC-1α expression.
• YY1 K183 lactylation disrupted mitochondrial homeostasis and alveolar epithelial barrier integrity.
• Therapeutic candidates targeting YY1 lactylation restored PGC-1α, improved mitochondrial function, and reduced ALI pathology.

Conclusions:

• Lactate-driven YY1 K183 lactylation is a key pathogenic mechanism in ALI.
• This lactylation disrupts PGC-1α-mediated mitochondrial quality control and epithelial barrier stability.
• Targeting the lactate-YY1 lactylation axis presents a promising therapeutic strategy for ALI and ARDS.