Activation of LAMP1-mediated lipophagy by sulforaphane inhibits cellular senescence and intervertebral disc degeneration.

BACKGROUND: Intervertebral disc degeneration (IDD) is a major cause of chronic low back pain, involving lipid dysregulation and cellular senescence in nucleus pulposus (NP) cells. However, the relationship between lipid accumulation and cellular senescence in IDD remain unclear. This study aims to investigate whether lipid accumulation promotes NP cell senescence and explore the role of LAMP1-mediated lipophagy in mitigating these effects. METHODS: Human and rat NP tissue samples were analyzed for lipid levels and senescence markers, including p16, p21 and p53. NP cells were treated with palmitic acid (PA) to induce lipid accumulation. Multi-omics analysis and machine learning were used to identify LAMP1 as a key regulator of lipid metabolism in NP cells. The effects of LAMP1 overexpression on lipid clearance and cellular senescence were evaluated in vitro. The natural compound sulforaphane (SFN) was applied to stimulate LAMP1-mediated lipophagy. LAMP1 knockdown was used to assess the role of LAMP1 in SFN-induced lipophagy and its impact on lipid accumulation and senescence. In vivo, SFN treatment was administered to rats with IDD induced by needle puncture. MRI, X-ray, and histological analysis were performed to evaluate the effects of SFN on disc degeneration, lipid accumulation, and senescence in NP tissue. RESULTS: Excessive lipid accumulation in degenerated NP tissues was observed, along with increased expression of senescence markers. Further experiments demonstrated that LAMP1 overexpression reduced lipid accumulation and senescence in NP cells. Notably, the natural compound sulforaphane enhanced LAMP1-mediated lipophagy, promoting lipid clearance and reducing senescence. In vivo, sulforaphane treatment in a rat IDD model reduced lipid accumulation and delayed IDD. CONCLUSION: Our findings suggest that LAMP1-mediated lipophagy plays a crucial role in inhibiting NP cell senescence and that sulforaphane can slow the progression of IDD by activating LAMP1. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study indicates that the therapeutic effects of sulforaphane in mitigating lipid accumulation and senescence can provide an effective treatment strategy for delaying the progression of IDD in the future.