Pyroptosis: mechanism and therapeutic strategies with intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is a major cause of low back pain, characterized by a complex interplay of inflammation, extracellular matrix degradation and various modes of cell death. Among these, pyroptosis, a highly inflammatory form of programmed cell death, has recently emerged as a critical pathogenetic mechanism. This review systematically elaborates on the role of pyroptosis in IDD, detailing its activation via the canonical and noncanonical inflammasome pathways in response to oxidative stress, mechanical load and metabolic disturbances. Here we highlight how pyroptosis synergizes with other pathological processes, creating a vicious cycle that accelerates disc degeneration. Furthermore, we critically evaluate promising therapeutic strategies that target pyroptosis, including small molecule inhibitors, biological agents, stem cell-derived extracellular vesicles and innovative biomaterial-based delivery systems designed to overcome the challenges of the avascular disc microenvironment. Finally, we discuss the translational potential and future directions of antipyroptosis therapies, proposing an integrated approach for managing IDD.