high-dose vitamin d supplementation attenuates nlrp3 inflammasome-mediated oxidative stress in a novel murine model of comorbid asthma and osteoporosis induced by vitamin d deficiency

While vitamin d deficiency (vdd) is implicated in both asthma and osteoporosis, the synergistic mechanisms linking these comorbidities remain unexplored. this study introduces a novel murine model of vdd-induced concurrent asthma and osteoporosis, uniquely addressing their bidirectional exacerbation through nlr family pyrin domain containing 3 (nlrp3) inflammasome activation and oxidative stress crosstalk.female c57 mice were stratified into control, bronchial asthma (ba), osteoporosis (op), ba+op, and vdd+ba+op groups, with therapeutic evaluation of low-dose (ld) and high-dose (hd) vitamin d supplementation. unlike prior studies, our results demonstrate that vdd amplifies airway resistance and bone microstructural deterioration via nlrp3-driven pyroptosis (elevated cleaved caspase-1, n-terminal gasdermin d and suppressed antioxidant defenses (reduced glutathione peroxidase and catalase, and elevated malondialdehyde). critically, hd supplementation reversed these effects more robustly than ld, restoring pulmonary compliance, trabecular integrity (bone volume/total volume: 0.0298 vs 0.0356 in vdd+ba+op), and suppressing inflammasome activity. mechanistically, we identify a feedforward loop wherein vdd-induced oxidative stress primes nlrp3 activation, which further exacerbates inflammation and bone resorption—a pathway uniquely mitigated by hd vitamin d. these findings provide the first evidence of hd vitamin d’s dual therapeutic efficacy in comorbid asthma-osteoporosis, offering a paradigm shift in targeting the nlrp3/oxidative stress axis for managing multifactorial inflammatory diseases.