Rosmarinic Acid Ameliorates Type 2 Diabetic Osteoporosis by Reducing NLRP3 Expression and Alleviating Osteoblast Pyroptosis via the FOXO1/TXNIP Signaling Pathway
Sixiang Feng, Runxun Ma, Yixun Huang, Libo Pan, Yangfan Guo, Yikai Wang, Zihao Chen, Enli Li, Yi‐tian Bu, Jian Luo, Jiahao Tang, Lei Yang
Abstract
Unlike postmenopausal osteoporosis, Type 2 diabetic osteoporosis (T2DOP) occurs in a chronic high-glucose, inflammatory microenvironment, increasing fracture risk. Emerging evidence links osteoblast pyroptosis to T2DOP pathogenesis. While rosmarinic acid (RA) exhibits antidiabetic and anti-inflammatory properties, its role in T2DOP remains unclear. We established a T2DOP mouse model using a high-fat diet and low-dose STZ, confirmed by micro-CT. RA's effects on osteoblast function and mitochondrial homeostasis were evaluated, with network pharmacology and molecular docking identifying potential targets. In vivo validation was performed through RA administration. Results showed pyroptosis activation and NLRP3 upregulation in T2DOP bone tissue. RA enhanced osteoblast proliferation, reduced pyroptosis, promoted mineralization, and mitigated mitochondrial dysfunction. The FOXO1/TXNIP pathway was identified as a key target, with RA suppressing NLRP3 activation via FOXO1/TXNIP modulation. This effect was reversed by FOXO1 inhibitor AS1842856. In vivo, RA preserved bone mass and microarchitecture in T2DOP mice. RA protects osteoblasts by improving mitochondrial function and inhibiting NLRP3-mediated pyroptosis through FOXO1/TXNIP signaling, offering a potential T2DOP treatment strategy.