Human molecular mechanisms of lumbar disc degeneration: A scoping review

Twenty-nine studies were selected for the synthesis of findings. Current evidence converges on dysregulated lipid metabolism, including impaired phosphatidylcholine synthesis and oxidized low-density lipoprotein signaling via LOX-1; ferroptosis and pyroptosis driven by iron overload and mitochondrial DNA-mediated inflammasome activation; and interleukins (IL-21, IL-17A) that enhance TNF-α-mediated catabolic and inflammatory signaling. Epigenetic regulators (SIRT1 and BRD4), posttranscriptional/translational proteins (TRIM21, Piezo1, YAP1, CHSY3, FSTL1, and IGFBP5), and noncoding RNAs further modulate extracellular matrix homeostasis, cell cycle progression, apoptosis, and inflammation, often through NF-κB and MAPK pathways. Despite their clinical relevance, the included studies had several major limitations: small sample sizes, limited phenotypic profiling and stratification, demographically unbalanced cohorts, and reliance on in vitro or animal models for experimental data. Future studies should integrate multi-omics, imaging, and clinical data to enhance mechanistic insight and support the development of targeted therapies for LDD.