Multi-omics reveals ferroptosis as a key mechanism in PM2.5-exacerbated periodontitis via gingival fibroblast damage.

PM2.5, a ubiquitous air pollutant, exacerbates periodontitis progression through mechanisms previously unclear. This study employed cytological and integrated transcriptomic-metabolomic analyses to investigate PM2.5's toxic effects on gingival fibroblasts. Results demonstrated that PM2.5 exposure decreased gingival fibroblasts viability, adhesion, and migration, while increased inflammation and disrupted mitochondrial homeostasis. Transcriptomics identified 7034 differentially expressed genes (DEGs) with 3834 upregulated and 3200 downregulated. KEGG enrichment revealed upregulated DEGs primarily associated with ferroptosis and ATP-dependent chromatin remodeling, while downregulated DEGs were enriched in extracellular matrix receptor interaction, focal adhesion, and PI3K-Akt signaling. Metabolomics identified 261 differentially expressed metabolites (DEMs) with 136 upregulated and 125 downregulated, which were involved in ferroptosis, glutathione metabolism, arginine biosynthesis, and glycerophospholipid metabolism. Mechanistically, PM2.5 induced ferroptosis in gingival fibroblasts via intracellular iron accumulation, lipid peroxidation, and imbalance of mitochondrial homeostasis, leading to cell death, which was suppressed by ferrostatin-1 (Fer-1). This study establishes a mechanistic link between environmental PM2.5 exposure and aggravated periodontitis, elucidating ferroptosis as a key contributor to gingival fibroblasts damage.