Iron dysregulation, ferroptosis, and oxidative stress in diabetic osteoporosis: Mechanisms, bone metabolism disruption, and therapeutic strategies

Table 3 The role of iron metabolism dysregulation in diabetic osteoporosis

Mechanism type	Key factors	Pathway	Impact on bone metabolism	Ref.
Iron overload	Iron ions (Fe2+/Fe3+)	Excess iron generates ROS via the Fenton reaction, causing oxidative stress and lipid peroxidation	Damages osteoblasts, inhibits their differentiation and function, reduces bone formation; promotes osteoclast differentiation, increasing bone resorption	Zang et al[59], Liu et al[62], Harrison et al[65]
Ferroptosis (iron-dependent cell death)	GPX4, SLC7A11, ROS	Iron-dependent cell death involving lipid peroxidation and antioxidant system imbalance	Induces bone cell death, disrupts bone tissue structure, and promotes the progression of osteoporosis	Yang et al[68]
Hepcidin dysregulation	Hepcidin, FPN1	Overexpression of hepcidin inhibits iron export protein FPN1, leading to intracellular iron accumulation	Increases iron content in bone marrow mesenchymal stem cells, inhibits their differentiation into osteoblasts, reduces bone formation	Zang et al[59]
Hyperglycemia-induced dysregulation	Hyperglycemia, AGEs, ROS	High-glucose environment promotes AGEs formation; AGEs bind to their receptors, inducing ROS production and iron metabolism dysregulation	Causes osteoblast dysfunction, enhances osteoclast activity, and exacerbates osteoporosis	Xie et al[71], Dludla et al[72], Zhao et al[73]

AGEs: Advanced glycation end products, glycation products formed in a hyperglycemic environment that bind to their receptors, inducing oxidative stress and inflammatory responses; Fenton reaction: A reaction where Fe²⁺ interacts with hydrogen peroxide (H₂O₂) to produce hydroxyl radicals (·OH), triggering oxidative stress; GPX4: Glutathione peroxidase 4, a key antioxidant enzyme that inhibits lipid peroxidation and prevents ferroptosis; Hepcidin: A hormone secreted by the liver that regulates systemic iron balance by binding to the iron export protein ferroportin 1, controlling iron absorption and distribution; SLC7A11: Encodes the light chain subunit of system Xc^-, facilitating the exchange of intracellular glutamate for extracellular cystine to maintain intracellular glutathione levels.