Abstract

The formation of intracranial aneurysms (IAs) is linked to metabolic problems and functional abnormalities in vascular smooth muscle cells (VSMCs). Berberine (BBR), a tetracyclic alkaloid having anti-inflammatory, antioxidant, and energy metabolism regulatory capabilities, has an unknown impact in IA progression. The purpose of this study is to look at the effects of BBR on IA development and the molecular mechanisms that drive it. An elastase-induced rat IA model was established as previously described, with in vivo measurements of aneurysm incidence, rupture rates, and artery structural integrity. An in vitro damage model was created by using primary VSMCs treated with Ang II. Inflammatory reactions, oxidative stress, mitochondrial function, and energy metabolism were investigated. The SIRT1/HMGB1/NF-κB signaling axis was investigated by Western blotting, immunofluorescence, pharmacological inhibition (EX-527), genetic manipulation (SIRT1 overexpression or HMGB1 knockdown/overexpression), and mitochondrial-targeted therapies (Antimycin A, MitoTEMPO). BBR dramatically reduced IA development and rupture in rats, reducing arterial inflammation and structural damage. In vitro, BBR restored Ang II-induced VSMC dysfunction, including mitochondrial depolarization, ROS overproduction, glycolytic shift, and inflammation, by upregulating SIRT1, increasing its binding to HMGB1, and decreasing HMGB1 acetylation, cytoplasmic translocation, and NF-κB activity. EX-527 eliminated these benefits, whereas SIRT1 overexpression replicated them, revealing SIRT1’s important involvement. Loss- and gain-of-function studies revealed that HMGB1 operates downstream of SIRT1, and that mitochondrial integrity is critical: Antimycin A inhibited BBR’s actions, but MitoTEMPO mimicked them. BBR promotes SIRT1 to deacetylate HMGB1, preventing its cytoplasmic translocation and NF-κB-mediated inflammation. Importantly, mitochondrial dysfunction caused by Ang II or IA disease is a primary driver of