Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Spinal cord injury (SCI) is a severe traumatic disorder that causes irreversible damage to the nervous tissue. This damage leads to neuronal ferroptosis, a type of cell death, which contributes to neuronal loss. Growth differentiation factor 15 (GDF15) is a cytokine that regulates cell proliferation, differentiation, and death. This study found that GDF15 was significantly increased in neuronal ferroptosis. Silencing GDF15 aggravated ferroptosis both in vitro and in vivo, suggesting that GDF15 may have a protective role against ferroptosis. The study also found that GDF15-mediated inhibition of neuronal ferroptosis is through p62-dependent Keap1-Nrf2 pathway. In SCI mice, knockdown of GDF15 exacerbated neuronal death, interfered with axon regeneration and remyelination, aggravated ferroptosis-mediated neuroinflammation, and restrained locomotor recovery. These findings suggest that GDF15 effectively alleviates neuronal ferroptosis post SCI via the p62-Keap1-Nrf2 signaling pathway and promotes locomotor recovery of SCI mice.

• 1
  GDF15 was significantly increased in neuronal ferroptosis and silencing GDF15 aggravated ferroptosis both in vitro and in vivo, suggesting a protective role.
• 2
  GDF15 inhibits neuronal ferroptosis through the p62-Keap1-Nrf2 pathway. rGDF15 treatment further promotes the expression of p62, followed by the increased protein levels of Nrf2 and HO-1 in vitro. Oppositely, knockdown of GDF15 in SCI mice significantly inhibited the p62-Keap1-Nrf2 signaling pathway and consequently aggravated ferroptosis.
• 3
  Knockdown of GDF15 in SCI mice led to more neuronal loss, axonal regeneration and remyelination were impeded, neuroinflammation was aggravated, and locomotor recovery was inhibited.