# From diabetes to dentistry: metformin targets mitochondrial-immune crosstalk to restore periodontal homeostasis

## TL;DR

Metformin, a diabetes drug, shows promise in treating periodontitis by targeting mitochondrial and immune interactions to reduce inflammation and promote bone regeneration.

## Contribution

This paper reviews metformin's novel mechanisms in periodontal therapy, including its effects on mitochondrial function, immune modulation, and bone regeneration.

## Key findings

- Metformin activates AMPK to enhance neutrophil and macrophage bactericidal activity.
- Metformin suppresses mTOR signaling to promote M2 macrophage polarization and reduce inflammation.
- Localized metformin delivery systems are being developed to improve periodontal therapeutic efficacy.

## Abstract

Metformin (MET), a first-line antidiabetic agent, exhibits significant therapeutic potential for periodontitis management due to its multifaceted pharmacological actions.

This review synthesizes current evidence on MET’s antimicrobial, anti-inflammatory, and osteogenic properties in the context of periodontitis. Mechanistically, MET primarily targets mitochondrial Complex I, inhibiting ATP production and activating AMPK. This AMPK activation enhances microtubule dynamics via CLIP170 phosphorylation, thereby boosting the bactericidal capacity of neutrophils and macrophages. Furthermore, MET suppresses mTOR signaling, which promotes M2 macrophage polarization, regulates autophagic flux, and inhibits NLRP3-mediated pyroptosis, collectively mitigating periodontal inflammation and tissue damage. In the realm of bone regeneration, MET upregulates key osteogenic markers and improves alveolar bone volume in preclinical models. Recent translational advances are focusing on the development of localized MET delivery systems, such as hydrogels, electrospun fibers, and MET-functionalized scaffolds, to enhance therapeutic efficacy at the site of disease.

MET represents a promising multifunctional agent for periodontitis therapy, effectively bridging antimicrobial and regenerative therapeutic strategies. However, several challenges remain, including the need to define optimal concentrations for osteogenesis and to obtain robust clinical validation for novel delivery systems. Future research should prioritize systematic dose optimization, mechanistic exploration beyond the canonical AMPK pathway, and the execution of large-scale clinical trials to translate these promising preclinical findings into established clinical practice.