Archives of oral biology · 2026
Fusobacterium nucleatum-induced endothelial ferroptosis promotes atherosclerosis.
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Deng Hanzhi, Wu Peiyao, Zhou Jieyu, Zhao Lei
Аннотация
OBJECTIVE: 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.
DESIGN: 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.
RESULTS: 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.
CONCLUSIONS: 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.
DESIGN: 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.
RESULTS: 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.
CONCLUSIONS: 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.