Selenomethionine alleviates aortic dissection via PGC-1α/NRF2/TFAM-mediated mitochondrial biosynthesis against ferroptosis: an experimental study

Background Aortic dissection (AD) is a cardiovascular disease with an extremely high mortality rate, and there is currently a lack of specific therapeutic drugs clinically. Selenomethionine (Set), known for its antioxidant and anti-inflammatory properties, has demonstrated promising potential in the treatment of cardiovascular diseases. Here, its therapeutic efficacy in AD and underlying mechanisms were explored. Methods The mouse model was established by BAPN induction. The effects of Set on aortic dilation, histopathology, and survival rate were evaluated. In vitro , PDGF-BB-induced phenotypic switching of vascular smooth muscle cells (VSMCs) was utilized. EdU assay, transwell migration assay, and lipid peroxidation experiments were conducted to analyze the impact of Set. Key molecular mechanisms were further validated through single-cell sequencing, transcriptomic analysis, and siRNA knockdown techniques. Results In vivo experiments demonstrated that Set significantly reduced the incidence and mortality of AD, suppressed aortic dilation, alleviated elastic fiber fragmentation, and inhibited collagen hyperplasia. In vitro , Set effectively attenuated PDGF-BB-induced proliferation, migration, and phenotypic switching of VSMCs. Single-cell sequencing revealed marked enrichment of ferroptosis-related genes in VSMCs from AD patients. Transcriptomic analysis indicated that Set substantially inhibited ferroptosis signaling and activated mitochondrial biogenesis pathways. Mechanistically, Set activated the PGC-1α/NRF2 pathway, upregulated GPX4 expression, reduced lipid peroxidation, and improved mitochondrial function, ultimately suppressing phenotypic switching of VSMCs. Notably, knockdown of GPX4 or PGC-1α weakened the inhibitory effects of Set on VSMCs phenotypic switching. Conclusions Set alleviated AD progression by suppressing ferroptosis-mediated phenotypic switching of VSMCs through targeted activation of the PGC-1α/NRF2/TFAM axis.