PDK4 drives abdominal aortic aneurysm by promoting smooth muscle cell metabolic reprogramming and NLRP3-mediated pyroptosis.

Summary

This mechanistic study identifies PDK4 as a key driver of AAA by reprogramming VSMC metabolism, impairing mitochondrial respiration, and activating the NLRP3 inflammasome and pyroptosis. VSMC-specific Pdk4 deletion curtailed AAA formation in mice, and pharmacologic NLRP3 inhibition attenuated disease, nominating PDK4 as a therapeutic target.

Key Findings

• PDK4 is upregulated in human and mouse AAA tissues.
• VSMC-specific Pdk4 deletion significantly reduces AAA formation in male mice.
• PDK4 reprograms VSMC metabolism, impairs mitochondrial respiration, and activates NLRP3 inflammasome–mediated pyroptosis.
• Genetic Pdk4 deletion or pharmacologic NLRP3 inhibition attenuates AAA progression in mice.

Clinical Implications

Although preclinical, targeting PDK4 or downstream NLRP3 pyroptosis could underpin first-in-class disease-modifying therapies for AAA, justify biomarker studies (PDK4 expression), and inform patient stratification in future trials.

Limitations

• Preclinical study; translational applicability to humans remains to be established.
• Sex-specific effects were reported in male mice; broader sex and species generalizability needs evaluation.

Future Directions

Develop selective PDK4 inhibitors suitable for vascular delivery, validate PDK4/NLRP3 biomarkers in human AAA cohorts, and design early-phase trials to test target engagement and progression slowing.