Tomatidine Alleviates Intervertebral Disc Degeneration by Activating the Nrf2/HO-1/GPX4 Signaling Pathway

Ze Li,1,2,* Pu Cheng,1,2,* Huifeng Xi,1,2,* Ting Jiang,1,2 Xiaohang Zheng,1,2 Jianxin Qiu,1,2 Yuhang Gong,1,2 Xinyu Wu,1,2 Shuang Mi,1,2 Yuzhen Hong,3 Zhenghua Hong,1,2 Weiwei Zhou1,2 1Department of Orthopaedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, People’s Republic of China; 2Bone Development and Metabolism Research Center of Taizhou Hospital, Linhai, Zhejiang Province, People’s Republic of China; 3School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, 430065, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiwei Zhou; Zhenghua Hong, Department of Orthopaedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Taizhou Linhai City, Zhejiang Province, People’s Republic of China, Email [email protected]; [email protected]: Intervertebral disc degeneration (IDD) is a leading cause of low back pain, and developing new molecular drugs and targets for IDD is a new direction for future treatment strategies. The aim of this study is to investigate the effects and mechanisms of tomatidine in ameliorating lumbar IDD.Methods: Nucleus pulposus cells (NPCs) exposed to lipopolysaccharides were used as an in vitro model to investigate changes in the expression of extracellular matrix components and associated signaling pathway molecules. A lumbar instability model was used to simulate IDD. Tomatidine (Td) was then administered intraperitoneally, and its effects were evaluated through histopathological analysis.Results: In vitro, Td significantly promoted ECM anabolism, inhibited ECM catabolism, and reduced oxidative stress and ferroptosis in LPS-stimulated NPCs. When Nrf2 expression was inhibited, oxidative stress and ferroptosis were exacerbated, and the protective effects of Td on NPCs were lost, suggesting the Nrf2/HO-1/GPX4 axis is critical for the therapeutic effects of Td. In vivo, histopathological analysis demonstrated that Td ameliorated IDD in a murine model.Conclusion: Td alleviates IDD in vitro and in vivo by activating the Nrf2/HO-1/GPX4 pathway to inhibit ferroptosis in NPCs. This mechanism suggests Td is a promising candidate for IDD treatment.Keywords: intervertebral disc degeneration, tomatidine, Nrf 2, GPX4, ferroptosis