MicroRNA–Ferroptosis–Spinal Cord Injury: A Complex Interplay in Neurodegeneration and Repair

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Abstract
Spinal cord injury (SCI) is a devastating neurological condition characterized by irreversible primary damage followed by a complex secondary injury cascade involving oxidative stress, neuroinflammation, iron dysregulation, and regulated cell death. Among these mechanisms, ferroptosis, a distinct, iron-dependent form of regulated cell death driven by lipid peroxidation and redox imbalance, is increasingly recognized as a critical mediator of neurodegeneration after SCI. The miRNAs play essential roles in neural injury responses by modulating inflammation, oxidative stress, and cell-death pathways. Growing evidence indicates that miRNAs closely regulate ferroptosis-related signaling networks following SCI, influencing key molecular targets including iron metabolism, antioxidant defense systems, and lipid peroxidation pathways. Conversely, ferroptotic stress may alter miRNA expression profiles, suggesting a bidirectional regulatory relationship. In addition, ferritinophagy, a selective autophagy pathway degrading ferritin via nuclear receptor coactivator 4 (NCOA4), has emerged as an important yet underexplored regulator of intracellular iron homeostasis and ferroptosis susceptibility in SCI. This review systematically summarizes current evidence on the molecular mechanisms linking miRNAs and ferroptosis in SCI, highlights how miRNA-mediated regulation of ferroptosis contributes to neuronal death, glial responses, and impaired regeneration, and discusses emerging therapeutic strategies targeting this axis to promote neuroprotection and functional recovery. By integrating recent experimental findings, we aim to provide mechanistic insight and identify translational opportunities for miRNA- and ferroptosis-based interventions in SCI.
Funding Information
  • National Science and Technology Council, Taiwan (114-2811-B-195 -003)
  • National Science and Technology Council, Taiwan (114-2811-B-195 -001)
  • National Science and Technology Council, Taiwan (112-2314-B-195-023-MY3)
  • National Science and Technology Council, Taiwan (112-2113-M-A49-004-)
  • National Science and Technology Council, Taiwan (113-2823-8-A49-001-)
  • National Science and Technology Council, Taiwan (111-2923-M-A49-002-MY3)
  • Mackay Memorial Hospital, Taiwan (MMH-E-114-12)
  • Mackay Memorial Hospital, Taiwan (MMH-E-115-12)
  • Mackay Memorial Hospital, Taiwan (MMH-E-107-05)
  • Ministry of Education (MoE), Taiwan

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