Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 24 4 2025 06 26 551 562 Pengtao Song Department of Pathology, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Affiliated Central Hospital of Huzhou University, Huzhou, China Wei Mao Department of Respiratory and Critical Medicine, Huzhou Traditional Chinese Medicine Hospital, Affiliated to Zhejiang Chinese Medical University, Huzhou, China Yinan Chen Department of Respiratory Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, China Zhicong Liu Department of Respiratory Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, China Yi Chen Department of Respiratory Medicine, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, China 2025 02 10 2025 03 14 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. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4339 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4339/2193