Ailanthone alleviates septic cardiomyopathy by attenuating MYST histone acetyltransferase 1 (MOF)-mediated H4K16 lactylation-driven inflammation.

Summary

The study uncovers a lactate–histone lactylation axis in septic cardiomyopathy: MOF catalyzes H4K16 lactylation that enriches at CXCL8/CCL2 promoters to drive inflammatory transcription. Pharmacologic glycolysis modulation with the HK2 inhibitor ailanthone reduced myocardial injury and improved cardiac function in septic mice, highlighting a tractable epigenetic-metabolic target.

Key Findings

• Lactate augments LPS-induced inflammation and apoptosis in cardiomyocytes.
• Histone H4K16 lactylation is upregulated and enriched at CXCL8 and CCL2 promoters to drive inflammatory transcription.
• MOF functions as a lactyltransferase catalyzing H4K16 lactylation.
• HK2 inhibition with ailanthone attenuates myocardial injury and improves cardiac function in septic mice.

Clinical Implications

Targeting the glycolysis–lactate–histone lactylation pathway (e.g., HK2 inhibition or MOF modulation) could emerge as an adjunct strategy for septic cardiomyopathy; translation will require safety profiling, dosing, and cardiac-specific targeting in humans.

Limitations

• Preclinical models may not capture the full spectrum of human septic cardiomyopathy phenotypes
• Potential off-target effects of ailanthone and systemic HK2 inhibition require safety evaluation

Future Directions

Validate MOF-dependent lactylation signatures in human septic myocardium and test selective MOF modulators/HK2 inhibitors in large-animal models and early-phase clinical trials.