Melatonin attenuates oxidative stress-induced ferroptosis of nucleus pulposus cells and intervertebral disc degeneration via PI3K/AKT-mTOR pathway

  • Int J Surg. 2026 Feb 24. doi: 10.1097/JS9.0000000000004980.
Zongyuan Deng  1  2 ,  Lutong Wang  1 ,  Tao Yu  1 ,  Guoyan Liang  1 ,  Zhengao Wang  3 ,  Xingchen Zhao  1 ,  Zhencong Zhang  1 ,  Xiang Long  1 ,  Xing Cheng  1 ,  Feng-Juan Lyu  4  5 ,  Peng Yu  6 ,  Chengyun Ning  6 ,  Yunbing Chang  1 ,  Yongxiong Huang  1 ,  Chong Chen  1
Affiliations
  • 1. Department of Spine Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 2. Department of Spine Surgery, Section II, Maoming People's Hospital, Maoming, China.
  • 3. Research Center of Biomass 3D Printing Materials, College of Materials and Energy, South China Agricultural University, Guangzhou, China.
  • 4. School of Medicine, South China University of Technology, Guangzhou, China.
  • 5. Joint Center for Regenerative Medicine Research of South China University of Technology and The University of Western Australia, School of Medicine, South China University of Technology, Guangzhou, China.
  • 6. School of Materials Science and Engineering, South China University of Technology, Guangzhou, China.
PMID: 41729690 DOI: 10.1097/JS9.0000000000004980
Abstract

Background: Intervertebral disc degeneration (IVDD) is a leading cause of low back pain and disability. Ferroptosis, an iron-dependent form of regulated cell death driven by oxidative stress, plays a critical role in IVDD pathogenesis. Melatonin, a neurohormone with antioxidative properties, has shown potential protective effects, but its precise mechanism of action remains unclear.

Methods: This study integrated multi-omics analyses, human NP specimens, cultured human NP cells, and a rat IVDD model induced by tert-butyl hydroperoxide (TBHP). Ferroptosis, oxidative stress, mitochondrial injury, and ECM metabolism were evaluated using histological staining, flow cytometry, ELISA, immunofluorescence, and western blotting. The involvement of melatonin receptors and PI3K/AKT-mTOR signaling was examined using pharmacological activation/blockade. Computational structural modeling was additionally employed to assess interactions between mTOR and ferroptosis-related proteins.

Results: Melatonin significantly inhibited TBHP-induced Ferroptosis in NP cells by restoring GSH levels, reducing Fe2⁺ accumulation and ROS generation, preserving mitochondrial morphology, and upregulating SLC7A11 and GPX4. Melatonin also ameliorated ECM metabolic imbalance by increasing Collagen II, aggrecan, and osteonectin, while suppressing MMP-9 and ADAMTS5. These protective effects were abolished by MT1/MT2 receptor antagonism or Akt phosphorylation inhibition, indicating pathway dependence. In vivo, melatonin attenuated disc degeneration, reduced Apoptosis, restored ECM components, and normalized ferroptosis-related markers. Multi-omics datasets and structural modeling further supported that melatonin regulates Ferroptosis through MT1/2-mediated activation of the PI3K/AKT-mTOR axis.

Conclusions: Melatonin mitigates IVDD by suppressing Ferroptosis and preserving ECM homeostasis through melatonergic receptor (MT1/MT2)-dependent activation of the PI3K/AKT-mTOR pathway. Notably, clinical and protein-level evidence suggests that MT1 may represent the predominant therapeutic target, supporting melatonin as a promising, low-toxicity candidate for delaying IVDD progression.

Keywords
PI3K/AKT-mTOR pathway; ferroptosis; intervertebral disc degeneration; melatonin; oxidative stress.
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