Nrf2 signaling pathway: focus on oxidative stress in osteoporosis

The nuclear factor erythrocyte 2-related factor-2 (Nrf2) signaling pathway is an important regulatory factor for bone homeostasis in osteoporosis. It is also regarded as a key pathway of antioxidant stress and is closely related to the pathological process of osteoporosis. Osteoporosis is a chronic metabolic bone disease characterized by an imbalance between osteoclast bone resorption and osteoblast bone formation, and oxidative stress is the core driving factor that induces bone metabolic imbalance. Studies have confirmed that the Nrf2 signaling pathway plays a key role in the pathological process of osteoporosis and in maintaining the homeostasis of the bone microenvironment. Here, we review the current knowledge about the role of the Nrf2 signaling pathway in osteoporosis and analyze its interaction with bone metabolism-related signaling pathways such as Wnt/β-catenin and NF-κB. By systematically integrating the existing research evidence, the therapeutic value of targeted activation of Nrf2 in improving bone metabolic imbalance, inhibiting osteoclastic activity and promoting bone formation is reviewed. Multiple studies have shown that the Nrf2 pathway, as a core antioxidant mechanism, effectively inhibits the excessive activation of osteoclasts and hyperresorption by antagonizing oxidative stress in osteoporosis, and dynamically regulates bone homeostasis. It forms a cross-regulatory network with key signaling pathways such as Wnt/β-catenin (promoting bone formation) and NF-κB (promoting inflammation), jointly influencing the level of oxidative stress and the balance of bone remodeling. Importantly, targeted activation of Nrf2 demonstrates significant therapeutic potential, capable of simultaneously promoting bone formation, inhibiting osteoclastic activity, and restoring the dynamic balance of bone metabolism, thereby providing multi-dimensional intervention in the pathological process of osteoporosis. The Nrf2 signaling pathway plays a core protective role in the pathogenesis of osteoporosis by regulating oxidative stress and related pathological links in multiple dimensions. Its interaction with key bone metabolic pathways provides a theoretical basis for the development of therapeutic strategies targeting Nrf2 and is expected to become a novel therapeutic target for improving bone metabolic imbalance.