Ketone Ester Attenuates Thoracic Aortic Aneurysm and Dissection by Suppressing Ferroptosis

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Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease lacking therapies that target underlying cell death pathways. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, has emerged as a key mechanism in vascular remodeling. We investigated whether exogenous ketosis induced by ketone ester (KE) supplementation can suppress ferroptosis and prevent TAAD. TAAD was induced in C57BL/6 mice using β-aminopropionitrile (BAPN). A subset of these mice received KE [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate, 20 g/L] in their drinking water starting on day 15 of the BAPN treatment. Human aortic smooth muscle cells (HASMCs) were treated with the GPX4 inhibitor Ras-Selective Lethal 3 (RSL3) and β-hydroxybutyrate (β-OHB) to investigate ferroptotic markers, lipid peroxidation, and labile iron levels. KE supplementation significantly reduced TAAD incidence (69% → 43%) and improved survival rate (52% → 73%), while preserving aortic structure and reducing elastic fiber fragmentation. Transcriptomic analyses of human TAAD datasets (GSE153434 and GSE52093) and single-cell RNA sequencing data (GSE155468) revealed ferroptosis signatures characterized by decreased GPX4 and increased expression of iron metabolism genes. Mechanistically, KE suppressed BAPN-induced iron accumulation and lipid peroxidation in vivo. In HASMCs, β-OHB inhibited ferroptosis induced by GPX4 inhibition, decreasing lipid peroxidation and labile iron levels. KE restored GPX4 and SLC7A11 expression while suppressing HO-1 in vivo, with effects dependent on Nrf2 signaling in vitro. In summary, ketone ester supplementation protects against TAAD by inhibiting VSMC ferroptosis via GPX4 induction and HO-1 suppression, highlighting a potential therapeutic strategy for aortic disease.

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