Fusobacterium nucleatum-Derived Isoleucine Exacerbates Aneurysm by Inducing Ferroptosis in Vascular Smooth Muscle Cells

BACKGROUND: Bacterial communities and their metabolites are increasingly recognized as key contributors to cardiovascular disease, yet their role and mechanistic involvement in abdominal aortic aneurysm (AAA) pathogenesis remain insufficiently defined. METHODS: Dental plaques from patients with AAA and matched healthy controls were subjected to metagenomic sequencing, and corresponding plasma samples underwent untargeted metabolomic profiling. In vivo, mice were topically exposed in the oral cavity to Fusobacterium nucleatum (Fn) followed by AngII (angiotensin II) infusion to evaluate its impact on AAA progression. A homologous recombination-based ilvE deletion strategy was used to confirm the role of Fn in isoleucine biosynthesis. Molecular assays were performed to assess ferroptosis-related signatures and histone acetylation in smooth muscle cells, while chromatin immunoprecipitation-quantitative polymerase chain reaction verified the specific acetylation target. In addition, dietary restriction of isoleucine was introduced in the AAA murine model to explore therapeutic relevance. RESULTS: Patients with AAA showed a marked enrichment of Fn in dental plaque, and topical application of Fn aggravated AngII-induced AAA in mice. Elevated plasma isoleucine concentrations were observed in both human AAA and experimental models. Genetic deletion of ilvE in Fn diminished bacterial isoleucine release and mitigated AAA development in mice. Mechanistic analyses revealed that Fn-derived isoleucine promoted ferroptosis in smooth muscle cells through H3K9ac (histone H3 lysine 9 acetylation)-dependent transcriptional activation of ACSL4 (acyl-CoA [coenzyme A] synthetase long-chain family member 4), a core regulator of ferroptosis. Dietary isoleucine restriction in the AngII-induced model reduced H3K9ac, suppressed ferroptosis, and alleviated aneurysmal progression. CONCLUSIONS: Fn-derived isoleucine drives ferroptosis in smooth muscle cells via H3K9ac-mediated activation of ACSL4, delineating a microbiota-metabolite-epigenetic axis in AAA pathogenesis and nominating dental plaque Fn abundance and circulating isoleucine as exploratory biomarker candidates requiring larger, independent validation.