Crosstalk of pathogenic signaling pathways in intervertebral disc degeneration: Epigenetic regulation and therapeutic implications

Intervertebral disc degeneration (IDD) is a significant cause of low back pain and functional disability, and its pathogenesis and progression involve various pathological processes such as inflammatory responses, oxidative stress, apoptosis, and dysregulation of extracellular matrix (ECM) metabolism. Increasing evidence indicates that multiple pathogenic signaling pathways are involved in the dysfunction and degeneration of intervertebral disc cells, and these pathways do not operate in isolation but collectively influence disease progression through complex crosstalk networks. Furthermore, epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs can further modulate the pathological state of intervertebral disc cells by regulating the activity of key signaling pathways and gene expression. Although related research continues to accumulate, current evidence is still mainly derived from animal experiments and cellular studies, with relatively limited clinical data. The dynamic interactions between different signaling pathways and their cross-relationships with epigenetic regulation still lack a clear integrated framework. This article integrates the pathological roles of major pathogenic signaling pathways in IDD from a network perspective, focusing on pathway crosstalk and its epigenetic regulatory mechanisms, and discusses their potential therapeutic implications and unresolved issues. It aims to deepen the understanding of the molecular mechanisms of IDD and provide theoretical support and research directions for the development of future targeted therapeutic strategies.