Rebuilding Mitochondrial Homeostasis and Inhibiting Ferroptosis: Therapeutic Mechanisms and Prospects for Spinal Cord Injury.

During the pathological process of spinal cord injury (SCI), ferroptosis is closely related to mitochondrial homeostasis. Following the occurrence of SCI, the interruption of local blood supply leads to mitochondrial damage within cells and a reduction in Adenosine triphosphate (ATP) production. This results in the loss of transmembrane ion gradients, causing an influx of Ca into the cells, which in turn generates a significant amount of Reactive oxygen species (ROS) and reactive nitrogen species. This leads to severe mitochondrial dysfunction and an imbalance in mitochondrial homeostasis. Ferroptosis is a form of programmed cell death that differs from other types of apoptosis, as it is dependent on the accumulation of iron and lipid peroxides, along with their byproducts. The double bond structures in intracellular polyunsaturated fatty acids (PUFA) are particularly susceptible to attack by ROS, leading to the formation of lipid alkyl free radicals. This accumulation of lipid peroxides within the cells triggers ferroptosis. After SCI, the triggering of ferroptosis is closely associated with the "death triangle"-a core network that catalyzes cell death through the interaction of three factors: local iron overload, collapse of antioxidant defenses, and dysregulation of PUFA metabolism (where PUFA are susceptible to attack by reactive ROS leading to lipid peroxidation). These three elements interact to form a central network driving cell death. In the pathological cascade of SCI, mitochondria serve as both a major source of ROS and a primary target of their attack, playing a crucial role in the initiation and execution of cellular ferroptosis. Mitochondrial homeostasis imbalance is not only a key inducer of the "death triangle" (such as the intensification of lipid peroxidation by mitochondrial ROS), but is also reverse-regulated by the "death triangle" (such as the destruction of mitochondrial structure by lipid peroxidation products). Through the cascade reaction of this triangular network, mitochondrial homeostasis imbalance and the "death triangle" jointly drive the progression of secondary damage. This study aims to synthesize the mechanisms by which various therapeutic approaches mitigate SCI through targeted regulation of mitochondrial homeostasis and inhibition of ferroptosis. Unlike previous research, we integrate the bidirectional regulatory relationship between "mitochondrial homeostasis disruption" and "ferroptosis" in SCI, and emphasize their importance as a synergistic therapeutic target. We not only elaborate in detail how mitochondrial homeostasis-including biogenesis, dynamics, and mitophagy-modulates the initiation and execution of ferroptosis, but also summarize recent strategies that simultaneously target both processes to achieve neuroprotection and functional recovery. Furthermore, this review highlights the translational potential of various treatments in blocking the pathological cascade driven by oxidative stress and lipid peroxidation. These insights provide a novel theoretical framework and propose combinatory therapeutic approaches, thereby laying the groundwork for designing precise and effective comprehensive treatment strategies for SCI in clinical settings.