Natural products protect against spinal cord injury by inhibiting ferroptosis: a literature review

Abstract

Spinal cord injury (SCI) is a severe traumatic condition that frequently results in various neurological disabilities, including significant sensory, motor, and autonomic dysfunctions. Ferroptosis, a recently identified non-apoptotic form of cell death, is characterized by the accumulation of reactive oxygen species (ROS), intracellular iron overload, and lipid peroxidation, ultimately culminating in cell death. Recent studies have demonstrated that ferroptosis plays a critical role in the pathophysiology of SCI, contributing significantly to neural cell demise. Three key cellular enzymatic antioxidants such as glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH), have been elucidated as crucial components in the defense against ferroptosis. Natural products, which are bioactive compounds mostly derived from plants, have garnered considerable attention for their potential therapeutic effects. Numerous studies have reported that several natural products can effectively mitigate neural cell death and alleviate SCI symptoms. This review summarizes fifteen natural products containing (-)-Epigallocatechin-3-gallate (EGCG), Proanthocyanidin, Carnosic acid, Astragaloside IV, Trehalose, 8-gingerol, Quercetin, Resveratrol, Albiflorin, Alpha-tocopherol, Celastrol, Hispolon, Dendrobium Nobile Polysaccharide, Silibinin, and Tetramethylpyrazine that have shown promise in treating SCI by inhibiting ferroptosis. Additionally, this review provides an overview of the mechanisms involved in these studies and proposes several perspectives to guide future research directions.

Keywords: GPx4; ROS; ferroptosis; natural product; spinal cord injury.

FIGURE 1

Natural products mediated anti-oxidative stress enzymatic systems in ferroptosis during the treatment of spinal cord injury. Ferroptosis is under control of GPX4-, FSP1-, and DHODH-dependent systems. GPX4 is the most important gatekeeper for ferroptosis and bolstered through the sustainment of GSH and cystine transportation of system Xc-activation. Cells are resistant to GPX4 inhibition through activating FSP1/CoQ10 system in cytoplasm to escape from ferroptosis. This GPX4-independent manner plays critical role in mitigating cellular ferroptosis. The third anti-oxidant system that DHODH-mediated ferroptosis protection in mitochondria is revealed. In the inner membrane of mitochondria, DHODH suppresses ferroptosis via the conversion of ubiquinone to ubiquinol that fights against oxidative damage on the phospholipid membrane. Total three gatekeepers presumably serve as potential targets for the treatment of spinal cord injury. Intriguingly, except alpha-tocopherol mitigates ferroptosis by targeting arachidonic acid 15-lipoxygenase (ALOX15), additional fourteen natural products inhibit ferroptosis all through GPX4-dependent pathway.