Harnessing natural products to target programmed cell death for intervertebral disc degeneration: Mechanisms and opportunity

Intervertebral disc (IVD) degeneration (IVDD) is a common age-related degenerative disorder and a leading cause of disability and mobility impairment in adults. It is characterized by dysfunction of nucleus pulposus cells (NPCs), annulus fibrosus (AF) cells (AFCs), and cartilage endplate (CEP) cells (CEPCs), triggered by aging, inflammation, and nutrient deprivation. These cellular alterations ultimately result in structural deterioration and functional impairment of the IVD. Programmed cell death (PCD), a key regulatory mechanism governing cell fate, precisely controls survival or elimination through highly conserved and specifically activated signaling cascades. Growing evidence indicates that natural products can modulate PCD pathways and slow IVDD progression, highlighting their potential as complementary therapies or novel drug candidates for IVDD management. In light of recent advances, this review systematically summarizes the mechanisms and interactive networks of six major PCD types: apoptosis, autophagy, ferroptosis, pyroptosis, necroptosis, and PANoptosis. It further explores how natural products regulate these processes to mitigate IVDD, as well as their prospects and strategies for clinical translation. Together, these insights provide a foundation for developing natural product-based therapeutics against IVDD.