Sting-Fam20c Axis Inhibits Gingival Pyroptosis In Periodontitis

To explore the non-canonical role of STING (distinct from TBK1/IRF3 signaling) in regulating gingival epithelial pyroptosis during periodontitis and its therapeutic potential. Single-cell RNA sequencing of 10 human gingival samples (GSE164241, 9 periodontitis, 13 healthy) identified STING+ epithelial subpopulations. Primary gingival epithelial cells (HOKs, n=5 donors) were treated with LPS and STING inhibitors. Lentiviral-mediated FAM20C knockout (KO) and overexpression (OE) models were analyzed via qPCR, Western blot, and immunofluorescence. Clinical validation used 25 gingival biopsies (15 periodontitis, 10 healthy) with ethics approval (YJSKY2024-401). STING+ basal epithelial cells exhibited 3.2-fold higher FAM20C expression compared to STING- cells (P<0.001), with FAM20C overexpression (OE) reducing CASPASE-1 activity by 37% (P<0.01) and suppressing pyroptosis. Conversely, FAM20C knockout (KO) significantly increased pyroptosis, as evidenced by 68% CASPASE-1 activation and 3.1-fold GSDMD fragmentation (P<0.001), while STING inhibition blocked LPS-induced FAM20C upregulation. Clinically, STING+/FAM20C+ basal cell co-localization was 4.5-fold higher in periodontitis versus healthy gingiva (76.3% vs. 18.9%, P<0.001), highlighting disease-specific pathway activation. The STING-FAM20C axis protects gingival epithelial integrity by inhibiting CASPASE-1/GSDMD-mediated pyroptosis, offering a novel therapeutic target for periodontitis.