Bempedoic acid directly binds and activates PPARα.

Summary

Using transcriptomics, biochemistry, and X-ray crystallography, this study shows that bempedoic acid directly binds the PPARα ligand-binding domain, stabilizes its active conformation, and induces fatty acid oxidation in hepatocytes and mouse liver. Activation of PPARα targets occurred independently of ACSVL1 conversion to bempedoyl-CoA, and fatty acid oxidation required PPARα, establishing direct PPARα activation as a core mechanism of action.

Key Findings

• Bempedoic acid directly binds the PPARα ligand-binding domain and stabilizes its active conformation (X-ray crystallography).
• BA robustly induces PPARα signaling and fatty acid oxidation in primary hepatocytes and mouse liver.
• Activation of PPARα targets occurs independently of ACSVL1-mediated conversion to bempedoyl-CoA; PPARα is required for BA-induced fatty acid oxidation.

Clinical Implications

Understanding BA as a direct PPARα activator informs combination strategies (e.g., with statins or fibrates), potential benefits in MASLD/NAFLD, and safety considerations when co-targeting nuclear receptors.

Limitations

• Preclinical work without direct human clinical outcome confirmation.
• Dose-response and long-term systemic effects were not fully explored in humans.

Future Directions

Assess BA–PPARα activation in human tissues, evaluate synergy or redundancy with fibrates, and explore indications in MASLD and atherogenic dyslipidemia.