ABHD17A-driven GLP1R depalmitoylation rewired G-protein coupling to impair periodontal ligament stem cell homeostasis in periodontitis

Background and Purpose: Periodontitis combines persistent inflammation with impaired periodontal regeneration. We investigated whether post-translational modification of glucagon-like peptide-1 receptor (GLP1R) regulates inflammatory-regenerative homeostasis in periodontal ligament stem cells (PDLSCs). Experimental Approach: GLP1R-Gαs and GLP1R-Gαi2 coupling was assessed using BRET and GTP-bound G-protein assays. Downstream cAMP/PKA, NF-κB, Wnt/β-catenin signaling, GLP1R palmitoylation, and osteogenic phenotypes were examined. Endogenous GLP1R C438A knock-in cells, proteomic screening, ABHD17A manipulation, experimental periodontitis models, and human samples were used for mechanistic and translational validation. Key Results: Inflammatory stimulation shifted GLP1R coupling from Gαs toward Gαi2 without substantially altering G-protein abundance, reducing cAMP/PKA activity, enhancing NF-κB signaling, suppressing Wnt/β-catenin signaling, and impairing osteogenesis. GLP1R palmitoylation was reduced in periodontitis, whereas C438A substitution largely abolished palmitoylation and reproduced the signaling imbalance. Proteomics identified ABHD17A as an inflammation-responsive GLP1R-associated depalmitoylase. ABHD17A depletion restored GLP1R palmitoylation, Gαs coupling, cAMP/PKA and β-catenin activity, while suppressing NF-κB signaling; these effects were attenuated in C438A cells. In vivo, GLP1R activation or ABHD17A silencing reduced periodontal bone loss and promoted regeneration. In human samples, the ABHD17A-GLP1R palmitoylation axis correlated with disease severity and therapeutic responsiveness. Conclusion and Implications: ABHD17A-dependent GLP1R C438 depalmitoylation drives pathological Gαs-to-Gαi2 coupling and links periodontal inflammation to regenerative failure, providing a potential therapeutic and biomarker framework for precision periodontitis treatment.