Inflammation-lipid interactions during intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is associated with inflammation and metabolic dysfunction, yet the direction of the relationship between lipid abnormalities and disc inflammation remains uncertain.

We searched PubMed, Scopus, and the Web of Science Core Collection from inception to 10 July 2026. The evidence was classified by causal direction, anatomical compartment, experimental model, and measured endpoint, with 58 primary reports included in the core evidence map.

Human studies of obesity, metabolic syndrome, and circulating lipids yielded inconsistent findings. Comparisons were also limited by differences in outcome definition, particularly between imaging-defined degeneration and diagnostic-code outcomes. Within disc tissue, lipid changes varied by context and involved cholesterol, lipid droplets, saturated fatty acids, membrane phospholipids, and sphingolipids. Experimental work provided clearer mechanistic evidence. Oxidised low-density lipoprotein activated LOX-1 signalling in cartilage endplate and nucleus pulposus cells. Cholesterol loading promoted endoplasmic reticulum stress, pyroptosis, matrix loss, and inflammatory macrophage responses, whereas saturated fatty acids induced organelle stress and NLRP3 inflammasome activation. Ferroptosis, senescence, and matrix degradation were treated separately from inflammation unless inflammatory signalling or immune responses were also measured. Evidence for the reverse direction was much more limited, consisting mainly of cytokine-related cholesterol accumulation and lipidomic changes in cultured disc cells without measurements of metabolic flux.

Because most mechanistic evidence comes from cell and animal models, these findings do not establish human causality or a sustained bidirectional feedback loop in IVDD. Longitudinal studies, metabolic flux analyses, local interventions, and clinically defined metabolic phenotypes are needed to clarify causality and therapeutic relevance.