Porphyromonas gingivalis Inhibits Ferroptosis and Promotes Malignant Phenotype in Oral Squamous Cell Carcinoma Cells via Upregulation of SIRT5.

Introduction: Oral squamous cell carcinoma (OSCC) exhibits aggressive behavior and poor prognosis. Porphyromonas gingivalis (P. gingivalis) affects the tumor microenvironment, but its role in ferroptosis inhibition in OSCC remains unclear. This study explores the impact of P. gingivalis on ferroptosis through SIRT5 upregulation.

Materials and methods: OSCC cell lines (Cal27, SCC9) were treated with the ferroptosis inducer RSL3, with or without P. gingivalis infection. Cell viability, ferroptosis markers (MDA, ROS, GPX4), and cell behavior (proliferation, migration, invasion) were assessed. SIRT5 and downstream targets (IDH2, GCLC) were analyzed using Western blot, qRT-PCR, and immunofluorescence. A SIRT5 knockdown model was used to evaluate its role in ferroptosis resistance.

Results: P. gingivalis infection increased OSCC cell survival, reduced ROS and MDA levels, enhanced GPX4 expression, and promoted proliferation, migration, and invasion. Elevated SIRT5 and its targets IDH2 and GCLC were observed. SIRT5 knockdown reversed ferroptosis resistance.

Conclusion: The findings suggest that P. gingivalis plays a critical role in promoting OSCC malignancy by inhibiting ferroptosis through the upregulation of SIRT5. This highlights the potential of targeting SIRT5 as a therapeutic strategy to counteract the effects of P. gingivalis in OSCC.