Advancing Intervertebral Disc Biology via Omics: Implications for Nucleus Pulposus Progenitor Cell‐Based Regeneration

ABSTRACT Background Intervertebral disc (IVD) degeneration (IDD) contributes to global disability and involves incompletely understood molecular processes. Recent advances in omics technologies help to unravel the complex biology of IDD and develop novel therapies. Methods This narrative review explores how omics approaches—particularly RNA sequencing—have advanced our understanding of IVD biology and how these findings contribute to leveraging the intrinsic regenerative potential of the IVD, with a specific focus on nucleus pulposus progenitor cells (NPPCs). Relevant literature addressing transcriptomic, genomic, proteomic, metabolomic, and epigenetic data, as well as emerging mult‐iomics approaches, was summarized. Results Single‐omics studies have provided insight into cellular heterogeneity, gene expression changes, genetic susceptibility loci, proteomic changes, metabolic alterations, and epigenetic regulation. Further, they have highlighted key pathways associated with extracellular matrix remodeling, inflammation, and progenitor cell depletion in IDD. Inconsistencies between TEK (the gene encoding TIE2) mRNA levels and TIE2 (Angiopoietin‐1 receptor) protein expression, discussed in this review, emphasize the limitations of single‐omics analyses and underscore the need for multi‐omics studies, which are currently underrepresented in the field. By enabling a system‐level understanding, multi‐omics offers a comprehensive framework to decode the networks driving IDD and identify biomarkers and therapeutic targets to restore disc function and reduce pain. Conclusions Although NPPCs hold promise for IVD regeneration, translational challenges such as cell survival and efficacy persist. Omics‐informed insights into the IVD microenvironment may support the development of combinatorial strategies, including co‐delivery of modulators to enhance NPPC survival and the effectiveness of therapies.