Understanding the Microenvironment of Intervertebral Disc Degeneration: A Comprehensive Review of Pathophysiological Insights and Therapeutic Implications

Intervertebral disc degeneration is a leading contributor to chronic back pain and disability worldwide. This review comprehensively explores the complex interplay of cellular, molecular, and biomechanical alterations within the disc microenvironment that underlie intervertebral disc degeneration pathophysiology. Emphasis is placed on extracellular matrix degradation, cellular senescence, inflammation, oxidative stress, angiogenesis, and multiple forms of programmed cell death including apoptosis, pyroptosis, and ferroptosis. An in-depth analysis of key signaling pathways and regulatory molecules illustrates how these processes disrupt homeostasis and drive disease progression. Additionally, the review highlights emerging therapeutic approaches aimed at modifying the disc microenvironment, including mesenchymal and notochordal cell-based therapies, senolytics, ferroptosis inhibitors, gene therapy, and biomaterial innovations such as hydrogels, scaffolds, and nanocarriers. These strategies target degenerative cascades at the molecular level and represent a shift toward regenerative and disease-modifying interventions. While several approaches show promise in preclinical and early clinical studies, challenges related to safety, delivery, and long-term efficacy remain. This review underscores the importance of integrating molecular insights with translational innovations to develop targeted therapies for intervertebral disc degeneration and guide future research efforts.