Targeting CTSS Rescues LPS ‐Induced Osteogenic Impairment in PDLSCs via Blocking NF ‐ κB ‐Dependent Inflammatory Responses

OBJECTIVE(S): This study aimed to elucidate the role of Cathepsin S (CTSS) in periodontitis, focusing on its dual impact on inflammation and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). MATERIALS AND METHODS: Integrated bioinformatics analysis of GEO datasets was performed, followed by experimental validation using PDLSCs from healthy individuals and periodontitis patients. Functional assays included CTSS knockdown/overexpression, LPS stimulation, osteogenic differentiation assessment, and evaluation of NF-κB signaling and inflammatory cytokines. RESULTS: Bioinformatics and experimental data consistently showed CTSS upregulation in periodontitis. CTSS knockdown enhanced osteogenic differentiation and mineralization while inhibiting LPS-induced NF-κB activation and pro-inflammatory cytokine expression (TNF-α, IL-1β, and IL-6); CTSS overexpression produced opposite effects. CONCLUSION(S): CTSS drives inflammation and suppresses PDLSC regenerative capacity via NF-κB activation, positioning it as a promising therapeutic target for periodontal tissue regeneration.