High glucose induces osteoblasts ferroptosis via the TXNIP/Trx-1/GPX4 pathway in type 2 diabetic osteoporosis.

Type 2 diabetic osteoporosis (T2DOP) is characterized by impaired bone formation and increased fracture susceptibility; however, the molecular mechanisms linking hyperglycemia to osteoblast dysfunction remain insufficiently defined. In this study, we demonstrate that high glucose (HG) triggers ferroptosis in osteoblasts through activation of the thioredoxin-interacting protein (TXNIP)/thioredoxin-1 (Trx-1)/glutathione peroxidase 4 (GPX4) pathway, leading to reduced cell viability, bioenergetic failure, and impaired osteogenic differentiation. HG exposure induced hallmark ferroptotic features-including excessive intracellular ferrous iron (Fe(2)⁺), elevated reactive oxygen species (ROS), lipid peroxidation, increased 4-hydroxynonenal (4-HNE), and acyl-CoA synthetase long-chain family member 4 (ACSL4), together with depletion of glutathione (GSH), GPX4, and ferritin heavy chain 1 (FTH1). Transcriptomic profiling identified TXNIP as a key upstream regulator under hyperglycemic conditions. Mechanistically, TXNIP directly interacts with and inhibits Trx-1, suppresses thioredoxin reductase-1 (TrxR1) activity, disrupts redox homeostasis, and ultimately inactivates GPX4, thereby promoting ferroptosis and osteogenic dysfunction. Silencing TXNIP restored antioxidant capacity, mitochondrial respiration, and mineralization in vitro. In a T2DOP rat model, systemic TXNIP knockdown significantly reduced oxidative injury, improved trabecular architecture and bone mineral density, and increased biochemical markers of bone formation. These findings identify TXNIP-dependent ferroptosis as a central mechanism of osteoblast impairment in diabetes and highlight the TXNIP/Trx-1/GPX4 axis as a promising therapeutic target for type 2 diabetic osteoporosis.