Heme-Induced Ferroptosis Promotes Human Lumbar Disc Degeneration Analyzed by MALDI-TOF MS



Liang Shan1, Ximing Xu2, Jing Zhang3, Peng Cai4, Han Gao1, Yingjie Lu5, Jiangang Shi2, Yinlong Guo3, Yue Su5


  1. Shanghai University of TCM: Shanghai University of Traditional Chinese Medicine
  2. The Second Military Medical University
  3. Shanghai Institute of Organic Chemistry
  4. Shanghai Institutes of Nutrition and Health CAS: Chinese Academy of Sciences Shanghai Institutes of Nutrition and Health
  5. Shanghai University of Traditional Chinese Medicine



Neovasculogenesis is a characteristic of degenerative lumbar discs, which makes extruded tissues exposed to heme-iron cytotoxicity (increased oxidative stress by ferroptosis). However, the present analyses for neovascularization are very complicated, and its mechanism of action is rarely reported.


Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was performed to analyze human degenerative lumbar discs. Then, clinical relevance was analyzed between MALDI-TOF MS results and Prrmann classification of degenerative discs. In order to explore the mechanism, a heme-induced ferroptosis effect was evaluated both at tissue and cell levels using high-resolution MALDI-TOF MS and molecular biology methods.


The spectra revealed that hemoglobin (Hb) and heme signals were highly increased, thus serving as biomarkers of vasculogenesis in degenerative tissues. Clinical relevance analysis demonstrated that the intensity of Hb and heme peaks was closely related to Pfirrmann classification of degenerative discs. Mechanically, increased heme catabolism and down-regulation of glutathione peroxidase 4 (GPX4) levels were detected in degenerative discs, reflecting an iron-dependent cell death or ferroptosis. Further, accuracy mass measurements confirmed that the levels of ferroptosis-related metabolites such as glutathione, arachidonic acid (AA), sphinganine, polyunsaturated fatty acid (PUFA), and tricarboxylic acid (TCA) cycle were significantly different between the degenerative and normal tissues, indicating the interior of degenerative tissues was a prooxidant environment. Moreover, the heme-induced ferroptosis was varied in human nucleus pulposus cells, and the underlying mechanism might be associated with the Notch pathway.


The neovascularization in degenerative discs may expose the tissues to high heme toxicity, which further induces the ferroptosis effect within the tissues and accelerates the degeneration progression of discs. This study is beneficial for the pathological mechanism in degenerative discs and facilitates the development of non-operative intervention for lumbar disc herniation (LDH).

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