Novel Regulatory Cell Death in Intervertebral Disc Degeneration

Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain. Its pathogenesis is highly complex and encompasses multiple pathological processes, including cellular dysfunction, extracellular matrix (ECM) degradation, inflammatory responses, oxidative stress, and aberrant mechanical loading. Traditionally, programmed cell death (PCD), particularly apoptosis and autophagy, has been regarded as a key contributor to IDD. However, with ongoing advances in this field, an expanding number of emerging forms of regulated cell death (RCD) have been identified and demonstrated to play critical roles in the initiation and progression of IDD. These advances have also provided new insights into the key molecular events underlying disc degeneration and have facilitated the identification of potential disease-modifying therapeutic targets. This review systematically summarizes five emerging RCD modalities, namely ferroptosis, cuproptosis, necroptosis, PANoptosis, and disulfidptosis, with particular emphasis on their mechanistic roles, key regulatory factors, signaling pathways, and patterns of interaction in IDD. Current evidence indicates that these RCD modalities not only independently contribute to cell death but may also converge through shared pathological nodes, including oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby producing synergistic amplification effects that further aggravate cell loss and matrix destruction. Regarding therapeutic strategies, a range of RCD-targeted pharmacological approaches has been reported to exhibit potential therapeutic value, including iron chelators, modulators of copper metabolism, inhibitors of the RIPK signaling pathway, antioxidants, and agents targeting PANoptosis-related signaling. These findings provide novel perspectives for the precision treatment of IDD. Nevertheless, most available studies remain limited to cellular and animal models, and the spatiotemporal expression patterns of the relevant signaling networks, their mechanisms of interaction, and their dynamic changes across different stages of degeneration remain to be further elucidated. Taken together, the identification of emerging RCD mechanisms has provided a more comprehensive framework for understanding the complex pathological processes of IDD. Furthermore, it has established a theoretical basis for the development of multi-target combinatorial intervention strategies and disease-modifying therapeutic paradigms, and may ultimately facilitate a shift in IDD management from symptomatic relief alone toward etiology-oriented and precision-based interventions.