Global Lactylome Reveals Lactylation-Dependent Mechanisms Underlying CXC Motif Chemokine Ligand 12 Expression in Pulmonary Endothelium During Acute Respiratory Distress Syndrome.
Summary
Using quantitative lactylome profiling, the authors link lactate-induced lysine lactylation to pulmonary endothelial dysfunction in ARDS. Hyperlactylation of ENO1 at K193 releases translational repression of CXCL12 mRNA and enhances ENO1 enzymatic activity, amplifying glycolysis; inhibiting lactylation mitigated experimental ARDS.
Key Findings
- Pulmonary lactate levels in ARDS patients correlated with disease severity and prognosis.
- Lactate drove pulmonary endothelial cell dysfunction via lysine lactylation; inhibiting lactylation reduced experimental ARDS and chemokine release.
- Quantitative lactylomics identified ENO1 K193 hyperlactylation, which released CXCL12 mRNA from translational repression and increased ENO1 enzymatic activity, amplifying glycolysis.
Clinical Implications
Targeting lactate-induced lysine lactylation or ENO1–CXCL12 signaling may offer endothelial-protective therapies in ARDS, complementing ventilatory strategies.
Why It Matters
This is a mechanistic advance identifying lysine lactylation of ENO1 as a nodal link between metabolic reprogramming and chemokine production in ARDS. It opens a druggable axis (lactate–Klac–CXCL12) for endothelial-targeted therapy.
Limitations
- Translational applicability to humans remains untested in interventional studies
- Potential off-target effects and feasibility of pharmacologic lactylation inhibition are not addressed
Future Directions
Develop selective modulators of lysine lactylation or ENO1–CXCL12 signaling and test endothelial-targeted strategies in preclinical ARDS models and early-phase trials.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- V - Mechanistic laboratory study with supportive patient correlation; no interventional clinical evidence.
- Study Design
- OTHER