Eriodictyol regulates LDHB to trigger mitophagy-mediated NLRP3 inflammasome inactivation as a therapeutic strategy for bone loss.
TL;DR
It is confirmed that ERI maintains bone homeostasis by regulating PINK1/Parkin-mediated mitophagy and suppressing NLRP3 inflammasome activation, which may provide a novel natural candidate for the treatment of bone loss-related diseases.
Abstract
Background
Imbalance of bone homeostasis triggers abnormal activation of osteoclasts and impaired osteogenic function, which further exacerbates bone resorption, reduces bone mass, and ultimately induces bone loss. Eriodictyol (ERI) possesses a wide range of biological activities and can effectively inhibit excessive bone destruction. Nevertheless, its role in ameliorating bone loss remains to be further elucidated. In this study, we identified ERI as a natural inhibitor of lactate dehydrogenase B (LDHB) that protects against bone loss, and revealed the molecular mechanism whereby ERI inhibits NLRP3 inflammasome activation via enhancing mitophagy.
Methods
To explore the relationship between ERI and osteoclast development and bone resorption, we performed CCK-8 assays, TRAcP staining, and scanning electron microscopy (SEM). RNA sequencing, western blotting, and qPCR were then carried out to dissect the molecular mechanisms by which ERI regulates osteoclast activity. The interaction between ERI and LDHB was evaluated using molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA). Functional manipulation of LDHB through both silencing and overexpression confirmed its regulatory role in osteoclasts. Finally, the protective effect of ERI against systemic bone loss was assessed in vivo using a lipopolysaccharide (LPS)-induced mouse model, with micro-CT analysis and histological immunostaining.
Results
Transcriptomic profiling indicated that ERI exerted suppressive impacts on osteoclast biological behavior, which was tightly linked to mitochondrial autophagy as well as the NLRP3 inflammatory complex. Mechanistically, ERI inactivated the NLRP3 inflammasome by enhancing mitophagy and reducing reactive oxygen species (ROS) formation. In addition, ERI directly and stably targets LDHB. Functional assays demonstrated that altered LDHB expression modulates the activation status of osteoclasts. Notably, ERI modulated osteoclast activity and mitophagy activation in a LDHB‑dependent manner. In vivo experiments further verified that ERI effectively alleviated bone loss triggered by LPS in mice.
Conclusions
Collectively, our findings confirm that ERI maintains bone homeostasis by regulating PINK1/Parkin-mediated mitophagy and suppressing NLRP3 inflammasome activation, which may provide a novel natural candidate for the treatment of bone loss-related diseases.