Qin Tianyu, Shi Ming, Xie Yongheng, Feng Naibo, Liu Chungeng, Chen Ke, Chen Yining, Zheng Wanli, Zhu Mingxi, Peng Songlin, Xiao Guozhi, Long Houqing
Division of Spine, Department of Orthopedic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, 518020, Guangdong, China.
Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, Guangdong, China.
J Orthop Translat. 2025 Jun 2;53:12-25. doi: 10.1016/j.jot.2025.05.010. eCollection 2025 Jul.
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.
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.
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.
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.
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.
椎间盘退变（IDD）是慢性下腰痛的主要原因，涉及髓核（NP）细胞中的脂质代谢失调和细胞衰老。然而，IDD中脂质积累与细胞衰老之间的关系仍不清楚。本研究旨在探讨脂质积累是否促进NP细胞衰老，并探索LAMP1介导的脂质自噬在减轻这些影响中的作用。
对人和大鼠的NP组织样本进行脂质水平和衰老标志物分析，包括p16、p21和p53。用棕榈酸（PA）处理NP细胞以诱导脂质积累。采用多组学分析和机器学习来确定LAMP1是NP细胞脂质代谢的关键调节因子。在体外评估LAMP1过表达对脂质清除和细胞衰老的影响。应用天然化合物萝卜硫素（SFN）刺激LAMP1介导的脂质自噬。通过敲低LAMP1来评估LAMP1在SFN诱导的脂质自噬中的作用及其对脂质积累和衰老的影响。在体内，对针刺诱导的IDD大鼠给予SFN治疗。进行磁共振成像（MRI）、X射线和组织学分析，以评估SFN对NP组织中椎间盘退变、脂质积累和衰老的影响。
观察到退变的NP组织中存在过多的脂质积累，同时衰老标志物的表达增加。进一步的实验表明，LAMP1过表达减少了NP细胞中的脂质积累和衰老。值得注意的是，天然化合物萝卜硫素增强了LAMP1介导的脂质自噬，促进了脂质清除并减少了衰老。在体内，大鼠IDD模型中的萝卜硫素治疗减少了脂质积累并延缓了IDD。
我们的研究结果表明，LAMP1介导的脂质自噬在抑制NP细胞衰老中起关键作用，并且萝卜硫素可以通过激活LAMP1来减缓IDD的进展。
本研究表明，萝卜硫素在减轻脂质积累和衰老方面的治疗作用可为未来延缓IDD进展提供有效的治疗策略。
