Porphyromonas gingivalis Promotes Neuroinflammation by Microglial Ferroptosis via NOX4/PPAR-α/PGC-1α Pathway

Background: Emerging evidence links Porphyromonas gingivalis (P.g), a keystone oral pathogen, neuroinflammation as a driver of Alzheimer's symptoms. This study aimed to investigate the molecular mechanism by which P.g triggers neuroinflammation and cognitive decline. Methods: Wild-type (WT) mice were orally gavaged with P.g for 8 weeks to evaluate cognitive function, neuronal integrity (p-Tau, hippocampal damage), and neuroinflammation. RNA sequencing analyzed brain transcriptomic, ferroptosis, and mitochondrial function after P.g induction was mainly analyzed. In vitro, the roles of NOX4/PPAR-α/PGC-1α pathway on ferroptosis, mitochondrial function, and inflammatory responses were evaluated after microglia were treated with P.g supernatant. Finally, NOX4-knockout mice were used to validate pathway specificity. Results: P.g administration in WT mice induced cognitive deficits, hippocampal neurodegeneration, p-Tau accumulation, and neuroinflammation, accompanied by dysregulated mitochondrial genes (NOX4, PPAR-α, and PGC-1α) and ferroptosis activation. P.g supernatant promoted microglial ferroptosis, mitochondrial dysfunction, and inflammatory cytokine release in vitro, which were reversed by NOX4 silencing. Mechanistically, NOX4 knockdown restored PPAR-α/PGC-1α signaling, suppressed ferroptosis, and mitigated inflammation in vitro. Critically, NOX4-knockout mice resisted P.g-induced cognitive impairment, neuronal loss, and neuroinflammatory responses in vivo. Conclusion: This study identified P.g-induced neuroinflammation and cognitive decline via microglial ferroptosis and mitochondrial dysfunction, which were regulated by the NOX4/PPAR-α/PGC-1α pathway. These findings highlight the link between oral health and brain pathology in Alzheimer's disease and propose NOX4 as a promising pharmacological target for cognitive preservation.