Background: Periodontitis is an immunoinflammatory disease. Ferroptosis is a type of inflammation-associated cell death. The article aims to investigate the expression, role, and mechanism of the ferroptosis-related gene acyl-CoA synthetase long-chain family member 6 (ACSL6) in periodontitis

Methods: Ferroptosis-related genes were identified using the Gene Expression Omnibus dataset and the Kyoto Encyclopedia of Genes and Genomes pathway. ACSL6 expression was validated using quantitative reverse-transcription polymerase chain reaction in patients with periodontitis. Human periodontal ligament fibroblasts (hPDLFs) were isolated and characterized. Following treatment, related experiments were performed to evaluate iron levels, reactive oxygen species (ROS) production, cell viability, ACSL6 expression, and ferroptosis-related proteins in hPDLFs.

Results: In this study, 185 genes were upregulated, and 102 were downregulated in the periodontitis group (p < 0.05). ACSL6, a ferroptosis-related gene, exhibited high expression levels in periodontitis tissues (p < 0.05). Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) upregulated ACSL6 (p < 0.05), downregulated ferroptosis-related genes (glutathione peroxidase 4 (p < 0.001) and cystine/glutamate transporter (Solute Carrier Family 7 Member 11) (p < 0.01)) and phosphor (p)-AMP-activated protein kinase (AMPK) (p < 0.05), reduced cell viability (p < 0.001), and elevated iron (p < 0.001) and ROS levels (p < 0.001) in hPDLFs. ACSL6 silencing could counteract the effects of P. gingivalis-LPS (p < 0.01). Furthermore, AMPK inhibitors lessen the effect of ACSL6 silencing (p < 0.01).

Conclusions: The ferroptosis-related gene ACSL6 was highly expressed in periodontitis tissues, and ACSL6 silencing enhanced viability and inhibited ferroptosis in P. gingivalis-LPS-mediated hPDLFs by upregulating the AMPK pathway.