SIRT3-activating, biodegradable poly-honokiol with high drug loading for thoracic aortic dissection therapy.

INTRODUCTION

Thoracic aortic dissection (TAD) is a life-threatening cardiovascular emergency with limited pharmacological treatment options.

OBJECTIVES

Building on the strong correlation between TAD and SIRT3 observed in our preliminary studies, we aim to leverage pharmacological interventions to enhance the clinical translation of this mechanism.

METHODS

Based on the SIRT3 activator honokiol, we synthesized a highly efficient, pH-responsive and biodegradable poly-honokiol prodrug synthesized via a metal-free phenol-yne click polymerization strategy, achieving an unprecedented drug-loading content of 83.65%, and subsequently investigated its pharmacological activity and underlying mechanisms using a β-aminopropionitrile (BAPN)-induced TAD model.

RESULTS

Compared with honokiol, poly-honokiol markedly improved survival and reduced TAD incidence in mice by preventing vascular smooth muscle cell (VSMC) loss. Mechanistic investigations reveal that poly-honokiol activates the mitochondrial deacetylase SIRT3, which induce the deacetylation of both the antioxidant enzyme SOD2 and the key ferroptosis regulator COX2, thereby reducing ferrous ion (Fe2+) accumulation and reactive oxygen species (ROS) levels while suppressing mitochondrial permeability transition pore (mPTP) opening, ultimately attenuating ferroptosis-induced VSMC loss.

CONCLUSION

Collectively, these findings demonstrate that poly-honokiol is a potent preventive candidate for TAD, offering both high drug-loading efficiency and targeted mitochondrial protection.