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

ABSTRACT 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.