The integrated stress response (ISR), regulated by general control nonderepressible 2 (GCN2), is essential for maintaining tissue homeostasis, yet its role in periodontitis remains poorly understood. Here, through transcriptomic analysis and immunohistochemistry of gingival biopsies from patients and a ligature-induced mouse periodontitis model, we demonstrate that GCN2-mediated ISR is activated in both human and mouse periodontitis and mainly functioned in macrophages. Using Gcn2-/- mice, we show that Gcn2 deletion exacerbates gingival inflammation and bone loss in experimental periodontitis. Mechanistically, bulk RNA-seq and in vitro assays revealed that the loss of GCN2 impairs autophagy and leads to overactivation of the NLRP3/CASPASE1 inflammasome pathway. Notably, local administration of halofuginone, a GCN2 activator, mitigates oral inflammation and tissue destruction in a GCN2-dependent manner. In summary, our work highlights the protective role of the GCN2-mediated ISR in oral mucosa and indicates GCN2 as a promising therapeutic target for periodontitis.
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