Ubiquitination in intervertebral disc degeneration: from mechanisms to potential therapeutic strategies

Intervertebral disc degeneration (IDD) is the primary cause of low back pain, imposing a heavy economic burden on individuals and society. The pathogenesis of IDD involves complex pathological processes. The interaction of extracellular matrix metabolism, regulated cell death (such as apoptosis, ferroptosis, pyroptosis, and autophagy), cell senescence, oxidative stress, and inflammatory response collectively contribute to the development of IDD. As a widespread post-translational modification, ubiquitination modulates various biological processes by regulating the activity and stability of proteins, including cell signal transduction, cell metabolism, and cell cycle. Recent studies have shown that ubiquitination plays an important role in the pathological process of IDD. This review systematically elucidates the molecular mechanisms by which ubiquitination regulates the progression of IDD. In addition, we summarize ubiquitination-based therapeutic strategies, including natural molecules, small-molecule compounds, extracellular vesicles, and bioactive materials. This review provides new insights and potential targets for understanding the molecular mechanisms of IDD as well as the treatment. The translational potential of this article: This study systematically clarifies the regulatory network of ubiquitination in IDD and identifies specific E3 ligases and DUBs as potential targets. Furthermore, we critically evaluate the advantages and challenges of ubiquitination-based therapeutic strategies, providing novel insights with both mechanistic depth and broad application prospects for breaking through the bottlenecks in the clinical treatment of IDD.