Investigating the potential role of YTHDC2 in hyperlipidemia-accelerated periodontitis

Periodontitis affects nearly half of adults worldwide and its prevalence is increasing among younger individuals. Hyperlipidemia is a recognized factor that worsens periodontitis. While the m6A reader YTHDC2 has been associated with metabolic and inflammatory conditions, whether it contributes to hyperlipidemia exacerbated periodontitis remains unknown. To model hyperlipidemia, we fed rats a high-fat diet (HFD) and then induced periodontitis by ligation with local Porphyromonas gingivalis (P. g ) application. In parallel, we treated human periodontal ligament stem cells (PDLSCs) with lipopolysaccharide (LPS) and palmitic acid (PA) to recreate a hyperlipidemic and inflammatory milieu. We measured YTHDC2 expression in periodontal tissues and examined its relationship with bone loss. We also knocked down YTHDC2 in PDLSCs using siRNA to evaluate its regulatory impact on IL-6 and TNF-α production. Hyperlipidemic rats developed more severe periodontitis and alveolar bone resorption, with YTHDC2 expression significantly reduced in gingival tissues and inversely correlated with bone loss. Mirroring these in vivo findings, LPS and PA stimulation suppressed YTHDC2 and elevated IL-6 and TNF-α in PDLSCs. Notably, YTHDC2 knockdown blunted the LPS/PA-induced increase in these inflammatory cytokines. Taken together, our study found that dysregulation of YTHDC2 expression is closely associated with alveolar bone resorption, which is a key pathological outcome of periodontitis. In addition, in vitro experiments showed that YTHDC2 knockdown suppressed the inflammatory response of PDLSCs under combined high-fat and inflammatory stimulation. These findings suggest that YTHDC2 may play a regulatory role in the pathological process by which hyperlipidemia exacerbates periodontitis, and they provide a preliminary experimental basis and research direction for further investigation of its molecular mechanisms.