Type 2 diabetes mellitus (T2DM) has the potential to exacerbate the progression of periodontitis, leading to alveolar bone resorption, tooth loss, and jaw atrophy [1]. Additionally, T2DM may elevate the risk of infection and failure following bone graft procedures, thereby affecting the outcomes of bone augmentation. The compromised osseointegration of dental implants associated with T2DM can reduce the long-term survival rates of these implants, posing significant challenges to dental implant treatments [2,3].

Bone marrow mesenchymal stem cells (BMMSCs) play a crucial role in maintaining bone homeostasis. The integration of BMMSCs with bone substitute materials in bone augmentation technology is anticipated to be an effective approach for reconstructing bone defects [4]. However, the hyperglycemic microenvironment characteristic of T2DM may induce mitochondrial dysfunction, leading to an overproduction of reactive oxygen species (ROS), which subsequently inhibits the proliferation and osteogenic differentiation of BMMSCs [5].

Glutathione peroxidase 7 (GPX7) is a crucial oxidoreductase enzyme. A deficiency in GPX7 results in elevated levels of ROS within cells and impedes the osteogenic differentiation of BMMSCs [6]. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key antioxidant transcription factor intricately associated with GPX7. A lack of NRF2 leads to increased bone resorption [7]. In the context of T2DM, chronic hyperglycemia markedly suppresses the expression of GPX7 and NRF2 in cells, leading to excessive ROS accumulation and consequently inhibiting the osteogenic differentiation of BMMSCs [8,9] Furthermore, NRF2 can bind to antioxidant response elements in the GPX7 gene promoter, enhancing GPX7 expression and improving stem cell activity [10]. Thus, the NRF2-GPX7 signaling pathway may represent a significant target for addressing oxidative stress and impaired osteogenesis in T2DM. Currently, there is a paucity of research on the NRF2-GPX7 pathway, and its role in regulating the osteogenic differentiation of BMMSCs has not been documented. Therefore, elucidating the mechanism of the NRF2-GPX7 pathway holds promise for identifying novel therapeutic targets for abnormal bone metabolism.

Metformin (MF) is a first-line pharmacological agent for the management of T2DM. Beyond its hypoglycemic properties, MF has been demonstrated to facilitate osteogenic differentiation in hyperglycemic conditions and enhance bone defect regeneration and new bone formation around implants in diabetic rats [11,12]. Despite these findings, the precise mechanisms underlying these effects remain unclear. Existing research indicates that MF can suppress the production of ROS within cells, modulate mitochondrial redox metabolism, and delay stem cell senescence. Currently, it is uncertain whether MF influences the osteogenic differentiation of BMMSCs by modulating oxidative stress in a T2DM environment, and limited research has explored the involvement of the NRF2-GPX7 signaling pathway.

This study aims to investigate whether MF inhibits oxidative stress and promotes osteogenic differentiation of BMMSCs in a T2DM context via the NRF2-GPX7 pathway.