Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.

Summary

Using LPS and CLP sepsis models plus in vitro systems, the authors identify lactate-driven lactylation of HADHA at K166 and K728 as a causal mechanism impairing mitochondrial function and cardiomyocyte contractility. SIRT1 and SIRT3 regulate these modifications, positioning lactylation as a therapeutic target for septic cardiomyopathy.

Key Findings

• Identified lactylation at HADHA K166 and K728 in septic myocardium and LPS-treated cells; levels were lactate dependent.
• HADHA lactylation inhibited enzymatic activity, impaired mitochondrial function and ATP production, reducing cardiomyocyte contractility in vitro and in vivo.
• SIRT1 and SIRT3 regulated HADHA lactylation; 1127 lysine lactylation sites were mapped with 83 differentially lactylated in sepsis.

Clinical Implications

Although preclinical, these findings suggest measuring or modulating cardiac lactylation and targeting SIRT1/3 or HADHA-lactylation could mitigate septic cardiomyopathy. They also reframe lactate as an active modifier, not just a biomarker.

Limitations

• Preclinical rodent and cell models; human validation of HADHA lactylation and therapeutic modulation is lacking.
• Use of H9c2 cell line may not fully recapitulate adult human cardiomyocyte biology.

Future Directions

Validate HADHA lactylation in human septic cardiomyopathy, test pharmacologic modulation (e.g., SIRT1/3 activators/inhibitors) and develop assays to monitor cardiac lactylation in patients.