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

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

  • J Orthop Translat. 2025 Jun 2:53:12-25. doi: 10.1016/j.jot.2025.05.010.
Tianyu Qin 1 2 3,  Ming Shi 4 5,  Yongheng Xie 1 3,  Naibo Feng 1 3,  Chungeng Liu 1 3,  Ke Chen 1 3,  Yining Chen 1 3,  Wanli Zheng 4,  Mingxi Zhu 4,  Songlin Peng 1 3 6,  Guozhi Xiao 3 7,  Houqing Long 1 3 6
Affiliations

Affiliations

  • 1 Division of Spine, Department of Orthopedic Surgery, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, 518020, Guangdong, China.
  • 2 Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, Guangdong, China.
  • 3 Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen, 518020, Guangdong, China.
  • 4 Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 528406, Guangdong, China.
  • 5 Department of Orthopedic, Zibo Central Hospital, Zibo, 255000, Shandong, China.
  • 6 Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China.
  • 7 Department of Biochemistry, Shenzhen Key Laboratory of Cell Microenvironment, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
PMID: 40525097 DOI: 10.1016/j.jot.2025.05.010
Abstract

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.

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