Abstract: Objective:?To investigate the role of c-Jun N-terminal kinase (JNK)/nuclear factor-κB (NF-κB)/Caspase-3 in kidney dysfunction related to periodontitis by establishing a mouse model of experimental periodontitis. Methods:?Twelve SPF-grade male C57 mice were randomly divided into a control group and a periodontitis group. Periodontitis was induced by ligating silk around the necks of the bilateral maxillary second molars. Four weeks later, the mice were sacrificed, and the three-dimensional structure of the alveolar bone was reconstructed using Micro-CT to analyze bone resorption. Histological changes in periodontal and kidney tissues were observed using hematoxylin-eosin (HE) and periodic acid-schiff (PAS) staining. Biochemical kits were used to detect kidney oxidative stress biomarkers malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and kidney function indicators creatinine (Cre) and albumin (Alb). Mitochondrial superoxide red fluorescent probe staining was employed to assess ROS levels in kidney tissues, while terminal dexynucleotidyltransferase-mediated dUTPnick end labeling (TUNEL) staining evaluated renal cell apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure expression levels of NF-κB, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), B-cell lymphoma 2 (Bcl-2), and in B-cell lymphoma-2-associated X protein (Bax) kidney tissues. Immunohistochemistry was performed to detect phosphorylated JNK (p-JNK), JNK, NF-κB, and Caspase-3 expressions in kidney tissues. Results: Compared to the control group, mice in the periodontitis group exhibited gingival hyperemia and swelling around the maxillary second molars. Micro-CT analysis revealed significant alveolar bone resorption in the periodontitis group, with an increased distance from the enamel-dentin junction to the alveolar ridge crest. Iirregular elongation of the gingival epithelial rete pegs, accompanied by resorption at the alveolar ridge crest, damage to the glomerular structure, and expansion of Bowman's space were showed. The thickening of the glomerular basement membrane and a reduction in the brush border of renal tubules in the periodontitis group were indicated. Biochemical assays demonstrated elevated MDA levels, decreased SOD and GSH levels in the kidney tissue of periodontitis mice (P＜0.05), along with increased serum levels of Cre and Alb (P＜0.05). Elevated ROS levels in the renal tissue of periodontitis mice was shown(P＜0.05). TUNEL staining results indicated an increase in the number of apoptotic renal cells in the periodontitis group (P＜0.05). qRT-PCR and immunohistochemistry showed that the expressions of IL-6, TNF-α, Bax, and NF-κB in the kidney tissue of periodontitis mice were increased (P＜0.05), while the expression of Bcl-2 was decreased (P＜0.05). The expression of JNK, p-JNK, NF-κB, and Caspase-3 was significantly elevated (P＜0.05). Conclusions: The JNK/NF-κB/Caspase-3 may play a crucial role in affecting renal cell apoptosis, contributing to kidney dysfunction induced by periodontitis.