Nystose treats intervertebral disc degeneration via the Nrf2 axis: a focus on oxidative stress and ferroptosis

Background Intervertebral disc degeneration (IDD) is the primary aetiology of chronic lower back pain and is driven by factors such as oxidative stress and nucleus pulposus (NP) cell dysfunction. Nystose (Nys), a key active oligosaccharide derived from Morinda officinalis How., has shown potential in treating degenerative diseases; however, its specific effect and underlying mechanism of action in IDD remain largely unexplored. Purpose This study aimed to investigate the therapeutic potential of Nys in IDD and elucidate whether its protective effects are mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) signalling axis. Methods Network pharmacology was used to identify potential targets of Nys. In vitro , Nys–Nrf2 binding was predicted via molecular docking and thermal shift assays, and the effects of this interaction on ROS levels, ferroptosis, and extracellular matrix (ECM) metabolism were evaluated in oxidatively stressed NP cells. These effects were verified using Nrf2 siRNA. The in vivo efficacy of Nys was assessed in a lumbar spine instability (LSI) mouse model. Results Network pharmacology identified Nrf2 as a core regulatory node. Nys suppressed ROS production and ferroptosis via iron metabolism regulation, which was driven by Nys binding to Nrf2 to promote its nuclear translocation. Nrf2 silencing abolished the ability of Nys to protect the ECM and exert antiferroptotic effects. In vivo testing confirmed that Nys shields the intervertebral disc from LSI-mediated damage through robust Nrf2 activation. Conclusion Nystose alleviates IDD by activating the Nrf2/HO-1/GPX4 signalling axis, which in turn inhibits oxidative stress and ferroptosis to restore ECM homeostasis. Nys represents a promising therapeutic candidate for IDD intervention.