A novel mechanism of FBXW7 in combating intervertebral disc degeneration: Mitigating ferroptosis in nucleus pulposus cells through the regulation of mitophagy.

With the aging of the global population, the prevalence of intervertebral disc degeneration (IVDD) disease is gradually increasing. This disease not only leads to a substantial reduction in the quality of life of patients but also imposes a considerable burden on the health care system. At present, the understanding of its pathogenesis is relatively limited, and in-depth research is urgently needed to identify effective treatment methods. One of the main causes of IVDD is the compression of the spine caused by body weight. The objective of this study was to investigate the potential regulatory mechanism underlying IVDD induced by excessive compression. Moreover, to investigate whether FBXW7 is involved in the regulation of mitophagy and ferroptosis, we used 1 MPa pressure to induce nucleus pulposus cell (NPC) degeneration and then constructed plasmids or small interfering RNAs to overexpress or knock down FBXW7. In addition, in vivo animal experiments were performed to verify the function of FBXW7. We found that FBXW7 expression was decreased in degenerative NP tissues. Compression promoted the initiation of mitophagy, but blocked autophagic flux and ultimately caused ferroptosis in NPCs. However, overexpression of FBXW7 can activate mitophagy, improve autophagic flux, and alleviate ferroptosis. Moreover, FBXW7 can bind to mTOR and promote its ubiquitination and degradation, thus increasing the expression of PINK1 and Parkin. Taken together, the results of both in vitro and in vivo experiments suggested that FBXW7 induced mitophagy, alleviated ferroptosis, and delayed IVDD via the mTOR signaling pathway.