Linezolid Attenuates Osteoclastogenesis and Reduces Periodontitis-Induced Bone Loss via Inhibition of Mitochondrial Translation

This is the authors' abstract. We don't add key points for this paper.

Objective To investigate the role of mitochondrial function in osteoclast differentiation and to evaluate the therapeutic potential of mitochondria-targeted interventions for periodontitis. The novelty of this study lies in our discovery that linezolid suppresses osteoclast differentiation by targeting the mitoribosome and inhibiting mitochondrial translation—a mechanism distinct from its conventional antibacterial activity. Methods We first analyzed single-cell RNA sequencing (scRNA-seq) data obtained from public databases, encompassing periodontal tissues from healthy individuals and chronic periodontitis patients to assess changes in osteoclast differentiation. The effects of linezolid, a mitoribosome-targeting drug, on osteoclast formation were then evaluated both in vitro using RAW264.7 cells and bone marrow-derived macrophages (BMMs), and in vivo using a rat periodontitis model treated with linezolid-loaded thermosensitive hydrogel (F-127). Results scRNA-seq revealed that osteoclast differentiation might be dependent on mitochondrial function, with key metabolic pathways and mitochondrial genes actively involved during osteoclastogenesis. Pharmacological inhibition of mitochondrial function by linezolid significantly suppressed osteoclast differentiation, as evidenced by reduced expression of osteoclast-specific markers. This inhibitory effect was reversed by the metabolic intermediate pyruvate, highlighting the critical role of mitochondrial metabolism in osteoclast formation. In vivo , a linezolid-loaded hydrogel significantly attenuated alveolar bone loss and inflammatory infiltration in a rat model of periodontitis. These findings suggest that targeting mitochondrial function may modulate osteoclast activity and provide therapeutic benefit in periodontal bone loss. Conclusion Linezolid-loaded hydrogel as a therapeutic strategy for mitigating alveolar bone loss in periodontitis. Clinical significance This study provides a new local therapeutic approach for periodontitis by targeting osteoclast mitochondrial metabolism, potentially complementing current infection‑focused strategies that lack direct bone‑protective effects.