n-3 polyunsaturated fatty acids delay intervertebral disc degeneration by inhibiting nuclear receptor coactivator 4-mediated iron overload.

n-3 polyunsaturated fatty acids (PUFAs) are closely related to the progression of numerous chronic inflammatory diseases, but the role of n-3 PUFAs in the intervertebral disc degeneration (IVDD) remains unclear. In this study, male C57BL/6 wildtype mice (WT group, n = 30) and fat-1 transgenic mice (TG group, n = 30) were randomly selected to construct the IVDD model. The results demonstrated that the optimized composition of PUFAs in the TG mice had a significant impact on delaying IVDD and cellular senescence of intervertebral disc (IVD). Mechanismly, n-3 PUFAs inhibited IVD senescence by alleviating NCOA4-mediated iron overload. NCOA4 overexpression promoted iron overload and weakened the pro-proliferation and anti-senescence effect of DHA on the IVD cells. Furthermore, this study futher revealed n-3 PUFAs downregulated NCOA4 expression by inactiviting the LGR5/β-catenin signaling pathway. This study provides an important theoretical basis for preventing and treating IVDD and low back pain.