Cuproptosis in spinal cord injury: emerging mechanisms and immunological relevance

Spinal cord injury (SCI) is a severe neurological disorder involving a two-phase pathological process. The primary injury results from direct mechanical trauma, while the secondary injury includes a cascade of cellular and molecular events such as excitotoxicity, oxidative stress, and inflammation. Recent studies have highlighted cuproptosis, a novel form of copper-dependent regulated cell death, as a significant contributor to secondary injury and immune dysregulation.

To summarize current research on cuproptosis in the context of spinal cord injury, clarify its molecular mechanisms and immunological effects, and explore its potential as a therapeutic target.

Relevant experimental and review studies were identified through database searches using keywords including cuproptosis, spinal cord injury, copper homeostasis, and regulated cell death. The review focuses on molecular mechanisms, mitochondrial dysfunction, immune responses, and key regulators such as FDX1, DLAT, ATP7A, and CTR1.

Following spinal cord injury, disruption of the blood-spinal cord barrier and inflammatory responses lead to copper accumulation, triggering cuproptosis. This process causes protein aggregation, mitochondrial dysfunction, and cell death, particularly in neurons, oligodendrocytes, and activated immune cells. During the acute phase, cuproptosis intensifies neuronal loss and inflammation. In the chronic phase, it may help eliminate persistently activated cells and contribute to scar remodeling. Cuproptosis also interacts with other forms of regulated cell death, such as pyroptosis and ferroptosis.

Cuproptosis plays an important role in SCI secondary injury and immune microenvironment remodeling. Targeting cuproptosis related pathways and restoring copper homeostasis may provide promising strategies for precision therapy.