Proteostasis Dysfunction and Heat Shock Protein Networks in Intervertebral Disc Degeneration: Molecular Mechanisms and Therapeutic Opportunities.

Intervertebral disc degeneration is a major pathological contributor to low back pain and functional impairment, yet its complex molecular mechanisms have not been fully elucidated. Heat shock proteins, as important molecular chaperones and core regulators of cellular stress responses, exhibit dual protective and pathogenic roles in the process of intervertebral disc degeneration. This review summarizes the expression changes and related regulatory networks of heat shock protein family members such as HSP70, HSP90, HSP27 and GRP78 in nucleus pulposus and annulus fibrosus cells, comprehensively discussing their involvement in the molecular mechanisms of intervertebral disc degeneration by influencing key processes such as cellular homeostasis, inflammatory responses, apoptosis, autophagy, and the synthesis and degradation of the extracellular matrix. Furthermore, this review highlights HSP-centered proteostasis regulation as an emerging therapeutic framework for IVDD and discusses how HSP modulation may be integrated with biomaterials, physical stimulation, and regenerative strategies. However, direct IVDD-specific evidence for certain HSP members remains limited, and this review also highlights current knowledge gaps and future research directions for HSP-centered proteostasis regulation.