Fusobacterium nucleatum-induced endothelial ferroptosis promotes atherosclerosis.

Authors

Hanzhi Deng, Peiyao Wu, Jieyu Zhou, Lei Zhao

Published in

Archives of oral biology. Volume 192. Pages 106776. Oct 07, 2026. Epub Oct 07, 2026.

Abstract

This study aimed to investigate whether Fusobacterium nucleatum (Fn), a key periodontal pathogen, induces ferroptosis in vascular endothelial cells and to evaluate its role in Fn-associated atherosclerosis progression.
Human umbilical vein endothelial cells (HUVECs) were exposed to Fn in the presence or absence of ferroptosis inhibitors. Oxidative stress, mitochondrial function, ferroptosis-related markers, and endothelial function were systematically assessed. An apolipoprotein E knockout (ApoE⁻/⁻) mouse model was used to evaluate the effects of Fn infection and Fer-1 treatment on atherosclerotic plaque formation and endothelial ferroptosis in vivo.
Fn significantly induced oxidative stress and mitochondrial dysfunction in HUVECs and enhanced endoplasmic reticulum-mitochondria contacts. Fn-treated HUVECs exhibited typical features of ferroptosis, including ferrous iron (Fe²⁺) accumulation, lipid peroxidation, downregulation of glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH), and upregulation of cyclooxygenase-2 (COX2) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Ferroptosis inhibitors attenuated these ferroptosis-related alterations, partially restored endothelial barrier function and nitric oxide (NO) production, and reduced the levels of inflammatory markers. In ApoE⁻/⁻ mice, Fn exacerbated atherosclerotic plaque formation and inflammatory responses, whereas Fer-1 attenuated these changes. Alterations in ferroptosis-related markers in the aortas of Fn-infected mice were similarly alleviated by Fer-1.
Fn-induced endothelial ferroptosis, accompanied by mitochondrial dysfunction and enhanced ER-mitochondria contacts, contributed to atherosclerosis progression. Ferroptosis inhibitors alleviated endothelial injury in vitro and in vivo, providing mechanistic evidence linking periodontal infection to cardiovascular disease and identifying ferroptosis as a potential therapeutic target.

PMID:
42860063
Bibliographic data and abstract were imported from PubMed on 12 Oct 2026.

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