SIRT3-activating, biodegradable poly-honokiol with high drug loading for thoracic aortic dissection therapy
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Updated: Jan 11, 2026
Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion
Published on: May 16, 2025
Xi'nan Qiao1, Daquan Wang2, Hanzhao Zhu1
1Department of Cardiovascular Surgery, Xijing Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710032, PR China.
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.
