AIM: To establish a reproducible experimental animal model for systemic lupus erythematosus (SLE)-associated periodontitis (PD), investigate the effects of SLE on PD and assess the therapeutic potential of alpha-ketoglutarate (αKG) for SLE-PD treatment. MATERIALS AND METHODS: An SLE-PD murine model was established via ligature-induced PD in MRL-lpr strain, with MRL/MpJ strain as a non-SLE control. The periodontal state was assessed using micro-CT, real-time PCR, histology, immunofluorescence and flow cytometry assays. αKG levels were analysed, and a thermoresponsive gel was designed as a periodontal dimethyl (DM)-αKG delivery system. αKG levels were analysed in gingival crevicular fluid (GCF) of PD patients with or without SLE. RESULTS: SLE significantly increased the periodontal inflammation and bone resorption in the SLE-PD model. αKG levels in GCF were lower in PD patients with SLE than in PD patients without SLE. Decreased αKG levels in the gingiva and macrophage M1/M2 imbalance were observed in SLE-PD mice. However, DM-αKG thermoresponsive gel effectively alleviated the periodontal inflammation, bone resorption and macrophage M1/M2 imbalance in SLE-PD mice. CONCLUSIONS: Our study established, for the first time, a novel SLE-PD murine model and revealed that SLE increases the severity of PD in vivo. Our findings highlight the therapeutic potential of αKG for SLE-associated PD.