Ferroptosis Contributes to Porphyromonas gingivalis-Induced Vascular Endothelial Injury

Introduction and aims Periodontitis and its keystone pathogen Porphyromonas gingivalis ( P. gingivalis ) are linked to cardiovascular disease (CVD), yet causative evidence remains limited. As endothelial injury is the earliest pathological event in CVD, exploring the direct impact of P. gingivalis on the vascular endothelium is a critical step toward establishing causality. Ferroptosis has been implicated in CVD, but its role in P. gingivalis -induced endothelial injury is unknown. This study thus aimed to explore the role of ferroptosis in P. gingivalis -induced vascular endothelial injury. Methods Endothelial injury was assessed in P. gingivalis -stimulated human umbilical vein endothelial cells (HUVECs) and mice by scanning electron microscopy, Oil Red O staining, hematoxylin-eosin (HE) staining, and immunohistochemistry. The ferroptosis phenotype was then investigated in P. gingivalis -infected HUVECs by real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. The role of SLC7A11 in regulating ferroptosis and injury of HUVECs was further examined, using RT-qPCR, Western blotting, immunofluorescence, ELISA, and flow cytometry. The protective effect of ferroptosis inhibition was finally validated in mice using ferrostatin-1 (Fer-1), assessed by HE, Western blotting and ELISA. Results P. gingivalis not only induces HUVECs injury but also causes structural disruption of the mouse aortic endothelium. P. gingivalis triggers ferroptosis through downregulation of SLC7A11 in HUVECs. Inhibition of ferroptosis by Fer-1 of restoring SLC7A11 expression effectively rescues the ferroptosis and injury of HUVECs. Furthermore, Fer-1 significantly ameliorates P. gingivalis -induced vascular endothelial injury in vivo . Conclusion P. gingivalis induced ferroptosis via SLC7A11 downregulation, which plays an important role in impairing vascular endothelial barrier integrity. Clinical relevance This study provides a mechanistic evidence for a causative link between periodontal infection and vascular endothelial injury and suggests ferroptosis as a potential target for future adjunctive therapies for reducing cardiovascular risk in periodontitis patients.