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

Abstract

BackgroundSpinal cord injury (SCI) is a severe traumatic disorder of the central nervous system (CNS) that causes irreversible damage to the nervous tissue. The consequent hemorrhage contributed by trauma induces neuronal ferroptosis post SCI, which is an important death mode to mediate neuronal loss. Growth differentiation factor 15 (GDF15) is a cytokine that regulates cell proliferation, differentiation, and death. However, the specific role of GDF15 in neuronal ferroptosis post SCI remains unknown.Materials and MethodsNeuronal ferroptosis in vitro was measured by detection of lipid peroxidation, glutathione, iron content, and reactive oxidative stress. In vivo, western blotting and immunofluorescence (IF) staining was utilized to measure ferroptosis post SCI. IF staining, TUNEL staining, hematoxylin-eosin staining, and Nissl staining were used to measure neurological damage. Finally, locomotor function recovery was analyzed using the Basso Mouse Scale and Louisville Swim Scale.ResultsGDF15 was significantly increased in neuronal ferroptosis and silencing GDF15 aggravated ferroptosis both in vitro and in vivo. Besides, GDF15-mediated inhibition of neuronal ferroptosis is through p62-dependent Keap1-Nrf2 pathway. In SCI mice, knockdown of GDF15 significantly exacerbated neuronal death, interfered with axon regeneration and remyelination, aggravated ferroptosis-mediated neuroinflammation, and restrained locomotor recovery.ConclusionGDF15 effectively alleviated neuronal ferroptosis post SCI via the p62-Keap1-Nrf2 signaling pathway and promoted locomotor recovery of SCI mice, which is suggested as a potential target on SCI pathogenesis and treatment.

A novel oxidative stress- and ferroptosis-related gene prognostic signature for distinguishing cold and hot tumors in colorectal cancer

“…NOX4 promotes ferroptosis in astrocytes through lipid peroxidation induced by oxidative stress by impairing mitochondrial metabolism in Alzheimer’s disease ( 24 ). Oxidative stress-dependent ferroptosis can be regulated by GDF15 post-spinal cord injury ( 25 ). It was also reported that the effects of nanomedicine in targeting ferroptosis and apoptosis can be enhanced by oxidative stress ( 26 ).…”

Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis

“…GDF15 was significantly increased in neuronal ferroptosis and silencing GDF15 aggravated ferroptosis both in vitro and in vivo. In spinal cord injury mice, knockdown of GDF15 significantly exacerbated neuronal death, aggravated ferroptosis-mediated neuroinflammation, and restrained locomotor recovery [73].…”

Ferroptosis is a new therapeutic target for spinal cord injury

“…In summary, the two most critical targets for the inhibition of Ferroptosis initiation, xCT and GPX4, have been modulated by NRF2. It has also been shown that Nrf2 can be used to regulate Ferroptosis to treat neurodegenerative diseases ( Song and Long, 2020 ), delay the progression of diabetic nephropathy (DN) ( Li S. et al, 2021 ) and prevent acute lung injury due to intestinal ischemia/reperfusion ( Dong et al, 2020 ), and it has been found that proanthocyanidins ( Zhou et al, 2020 ), alginose ( Gong et al, 2022 ), metformin ( Wang H. et al, 2020 ), and growth differentiation factor-15 ( Xia et al, 2022 ) are all inhibited by NRF2. These materials have been found to inhibit Ferroptosis through the Nrf2 pathway to treat SCI, but the specific downstream target proteins and enzymes that these substances affect through the Nrf2 pathway to inhibit Ferroptosis to treat SCI have not been clearly investigated.…”

“…And the knockdown of GDF-15 significantly exacerbated Ferroptosis. Subsequent researchers have found that GDF-15 inhibits Ferroptosis by activating the p62-Keap1-Nrf2 signaling pathway, thereby improving motor recovery in SCI ( Xia et al, 2022 ). However, other modulatory effects of GDF-15 on Ferroptosis and neuroinflammation in the neurocloud after SCI remain uncertain, and therefore further studies on the modulatory effects of GDF-15 are needed in the future.…”

“…Glucose-lowering drugs Upregulated GPX4, Nrf2 (Ma et al, 2021) Downregulation of MDA (Zeng et al, 2019) Trace elements Zinc Trace elements Upregulation of GSH, GPX4, Nrf2 (Ge et al, 2021) Downregulation of ROS (Ge et al, 2021) Selenium Trace elements Upregulation of GPX4 FSP1 (Chen Y. X. et al, 2022) Downregulation of MDA 4-HNE (Ge et al, 2021) miRNA miRNA-672-3p RNA Upregulates FSP1 Stem cell transplantation lncRNA-Gm36569 RNA Upregulates FSP1 (Shao et al, 2022) Cytokines GDF-15 Neuroprotective factor Upregulated Nrf2 (Xia et al, 2022) New synthetic substances SRS16-86 Small molecule Ferroptosis inhibitors Upregulates xCT, GSH, GPX4 DFO Iron chelator Upregulates xCT, GSH, GPX4 (Yao et al, 2019) Liproxstatin-1 Ferroptosis Inhibitors Upregulates xCT, GPX4, FSP1 (Fan et al, 2021) Ferrostatin-1 Ferroptosis Inhibitors Downregulation of Iron, ROS, IPEB2, PTGS2 (Ge et al, 2022) 4. Possible problems in the clinical translation of Ferroptosis inhibitors for the treatment of spinal cord injury…”