Paeonol mitigates age-related osteoporosis via mitophagy-mediated NLRP3 inflammasome inhibition

Age-related osteoporosis, a progressive skeletal disorder inherent to aging, is pathologically defined by diminished bone mass and deteriorated bone microarchitecture, resulting in heightened skeletal fragility. Despite extensive research, effective therapeutic interventions for age-associated bone loss remain limited. Accumulating evidence indicates that aging-induced immune dysregulation contributes significantly to chronic low-grade inflammation, thereby exacerbating osteoporotic progression. In this study, we identify Paeonol (PAE) as a potent mitigator of senile osteoporosis, acting through the modulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome/mitophagy axis. We demonstrate that PAE ameliorates aging-induced bone loss in the NLRP3 inflammasome-dependent manner by enhancing mitophagic flux. Specifically, PAE facilitates the clearance of dysfunctional mitochondria, thereby suppressing NLRP3 inflammasome activation and subsequent inflammatory responses. Notably, pharmacological or genetic inhibition of mitophagy abrogates the protective effects of PAE, as evidenced by the attenuated suppression of NLRP3 inflammasome activation and the diminished preservation of bone mass in aged murine models. These findings highlight the critical interplay between mitophagy and NLRP3 inflammasome in age-related bone loss and suggest that PAE-mediated enhancement of mitochondrial quality control represents a promising therapeutic strategy for osteoporosis management.