Research Progress on Solute Carrier Family 7 Member 11 Protein Regulation of Ferroptosis in Neurodegenerative Diseases

Jiaxian Liang; Jianwen Zhi; Bo Ning

doi:10.54097/mj9hbt81

Authors

Jiaxian Liang
Jianwen Zhi
Bo Ning

DOI:

https://doi.org/10.54097/mj9hbt81

Keywords:

SLC7A11, System Xc−, Ferroptosis, Neurodegenerative Diseases, Oxidative Stress, Glutathione Metabolism

Abstract

Solute carrier family 7 member 11 (SLC7A11) plays a crucial role in regulating ferroptosis and is closely associated with neurodegenerative diseases (NDDs) such as Alzheimer's disease and Parkinson's disease. As a key component of the cystine/glutamate antiporter (System Xc−), SLC7A11 inhibits lipid peroxidation and ferroptosis by mediating cystine uptake and glutathione synthesis. In NDDs, downregulation or dysfunction of SLC7A11 leads to decreased neuronal antioxidant capacity and exacerbated ferroptosis, thereby promoting disease pathogenesis and progression. Therefore, targeting SLC7A11 or ferroptosis-related pathways may represent novel therapeutic strategies for NDDs. This review systematically summarizes the specific mechanisms of SLC7A11 in NDDs, linking its function to the pathological mechanisms of NDDs through the emerging concept of "ferroptosis," thereby constructing an "SLC7A11-ferroptosis-neurodegenerative disease" association model and identifying SLC7A11 as a potential key molecular node connecting disease pathology with this mode of cell death.

Downloads

Download data is not yet available.

References

[1] TEMPLE S. Advancing cell therapy for neurodegenerative diseases [J]. Cell Stem Cell, 2023, 30(5): 512-529.

[2] DUGGER B N, DICKSON D W. Pathology of Neurodegenerative Diseases [J]. Csh Perspect Biol, 2017, 9(7): 34-45.

[3] JIANG X, STOCKWELL B R, CONRAD M. Ferroptosis: mechanisms, biology and role in disease [J]. Nature Reviews Molecular Cell Biology, 2021, 22(4): 266-82.

[4] TANG D, CHEN X, KANG R, et al. Ferroptosis: molecular mechanisms and health implications [J]. Cell Research, 2020, 31(2): 107-25.

[5] XIAO F, LI H-L, YANG B, et al. Disulfidptosis: A new type of cell death [J]. Apoptosis, 2024, 29(9-10): 1309-29.

[6] XUE Q, KANG R, KLIONSKY D J, et al. Copper metabolism in cell death and autophagy [J]. Autophagy, 2023, 19(8): 2175-95.

[7] YAN Y, TENG H, HANG Q, et al. SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells [J]. Nature Communications, 2023, 14(1):23-34.

[8] WANG G, QIN S, ZHENG Y, et al. T-2 Toxin Induces Ferroptosis by Increasing Lipid Reactive Oxygen Species (ROS) and Downregulating Solute Carrier Family 7 Member 11 (SLC7A11) [J]. Journal of Agricultural and Food Chemistry, 2021, 69(51): 15716-27.

[9] KOPPULA P, ZHUANG L, GAN B Y. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy [J]. Protein Cell, 2021, 12(8): 599-620.

[10] YAN Y L, TENG H Q, HANG Q L, et al. SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells [J]. Nat Commun, 2023, 14(1): 68-39.

[11] LIU J Y, XIA X J, HUANG P. xCT: A Critical Molecule That Links Cancer Metabolism to Redox Signaling [J]. Mol Ther, 2020, 28(11): 2358-66.

[12] WANG L, LIU Y, DU T, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc– [J]. Cell Death & Differentiation, 2019, 27(2): 662-675.

[13] LEE M H, SAHOTA A, WARD M D, et al. Cystine Growth Inhibition Through Molecular Mimicry: a New Paradigm for the Prevention of Crystal Diseases [J]. Current Rheumatology Reports, 2015, 17(5): 79-87.

[14] FRATERNALE A, PAOLETTI M F, CASABIANCA A, et al. GSH and analogs in antiviral therapy [J]. Molecular Aspects of Medicine, 2009, 30(1-2): 99-110.

[15] SONG X, ZHU S, CHEN P, et al. AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System Xc– Activity [J]. Current Biology, 2018, 28(15): 2388-99.e5.

[16] YANG T, ZHANG F. Targeting Transcription Factor Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) for the Intervention of Vascular Cognitive Impairment and Dementia [J]. Arteriosclerosis, Thrombosis, and Vascular Biology, 2021, 41(1): 97-116.

[17] JIANG X J, STOCKWELL B R, CONRAD M. Ferroptosis: mechanisms, biology and role in disease [J]. Nat Rev Mol Cell Bio, 2021, 22(4): 266-82.

[18] TANG D L, CHEN X, KANG R, et al. Ferroptosis: molecular mechanisms and health implications [J]. Cell Res, 2021, 31(2): 107-25.

[19] LIANG D G, MINIKES A M, JIANG X J. Ferroptosis at the intersection of lipid metabolism and cellular signaling [J]. Mol Cell, 2022, 82(12): 2215-27.

[20] WANG Z J, SHEN N, WANG Z, et al. TRIM3 facilitates ferroptosis in non-small cell lung cancer through promoting SLC7A11/xCT K11-linked ubiquitination and degradation [J]. Cell Death Differ, 2024, 31(1): 53-64.

[21] LI P, YU J, HUANG F, et al. SLC7A11-associated ferroptosis in acute injury diseases: mechanisms and strategies [J]. Eur Rev Med Pharmaco, 2023, 27(10): 4386-98.

[22] ZHANG X Q, ZHENG X C, YING X, et al. CEBPG suppresses ferroptosis through transcriptional control of in ovarian cancer [J]. J Transl Med, 2023, 21(1): 21-33.

[23] LIN F Y, CHEN W Y, ZHOU J H, et al. Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury [J]. Cell death & disease, 2022, 13(3): 57-67.

[24] TANG J N, LONG G, HU K, et al. Targeting USP8 Inhibits O-GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT [J]. Adv Sci, 2023, 10(33): 1299-1302.

[25] SCHELTENS P, DE STROOPER B, KIVIPELTO M, et al. Alzheimer's disease [J]. The Lancet, 2021, 397(10284): 1577-1590.

[26] GRAFF-RADFORD J, YONG K X X, APOSTOLOVA L G, et al. New insights into atypical Alzheimer's disease in the era of biomarkers [J]. The Lancet Neurology, 2021, 20(3): 222-234.

[27] FJELL A M, MCEVOY L, HOLLAND D, et al. What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus [J]. Progress in Neurobiology, 2014, 117: 20-40.

[28] DETURE M A, DICKSON D W. The neuropathological diagnosis of Alzheimer’s disease [J]. Molecular Neurodegeneration, 2019, 14(1): 1121-1134.

[29] LANE H Y, LIN C H. Diagnosing Alzheimer's Disease Specifically and Sensitively With pLG72 and Cystine/ Glutamate Antiporter SLC7A11 AS Blood Biomarkers [J]. Int J Neuropsychoph, 2023, 26(1): 1-8.

[30] CANAL-GARCIA A, BRANCA R M, FRANCIS P T, et al. Proteomic signatures of Alzheimer's disease and Lewy body dementias: A comparative analysis [J]. Alzheimers Dement, 2025, 21(1): 23-37.

[31] GU X H, SONG Y Q, LIU X, et al. METTL14-Mediated m6A Modification of Represses Ferroptosis in Alzheimer's Disease via Inhibiting GDF15 Ubiquitination [J]. Front Biosci-Landmrk, 2024, 29(8): 78-85.

[32] PUSCHMANN A. New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism [J]. Current Neurology and Neuroscience Reports, 2017, 17(9): 98-103.

[33] TOLOSA E, WENNING G, POEWE W. The diagnosis of Parkinson's disease [J]. The Lancet Neurology, 2006, 5(1): 75-86.

[34] SU D, GAN Y, ZHANG Z, et al. Multimodal Imaging of Substantia Nigra in Parkinson's Disease with Levodopa‐Induced Dyskinesia [J]. Movement Disorders, 2023, 38(4): 616-25.

[35] TRIST B G, HARE D J, DOUBLE K L. Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease [J]. Aging Cell, 2019, 18(6): 104-112.

[36] QIU Y, CAO Y, CAO W, et al. The Application of Ferroptosis in Diseases [J]. Pharmacological Research, 2020, 159: 104919.

[37] ALKANLI S S, ALKANLI N, AY A, et al. CRISPR/Cas9 Mediated Therapeutic Approach in Huntington’s Disease [J]. Molecular Neurobiology, 2022, 60(3): 1486-1498.

[38] TYSNES O-B, STORSTEIN A. Epidemiology of Parkinson’s disease [J]. Journal of Neural Transmission, 2017, 124(8): 901-905.

[39] TABRIZI S J, GHOSH R, LEAVITT B R. Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease [J]. Neuron, 2019, 101(5): 801-819.

[40] GRATUZE M, CISBANI G, CICCHETTI F, et al. Is Huntington's disease a tauopathy? [J]. Brain, 2016, 139(4): 1014-1025.

[41] HANDSAKER R E, KASHIN S, REED N M, et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease [J]. Cell, 2025, 188(3): 623-39.e19.

[42] JOMOVA K, MAKOVA M, ALOMAR S Y, et al. Essential metals in health and disease [J]. Chemico-Biological Interactions, 2022, 367: 110173.

[43] FJODOROVA M, NOAKES Z, DE LA FUENTE D C, et al. Dysfunction of cAMP–Protein Kinase A–Calcium Signaling Axis in Striatal Medium Spiny Neurons: A Role in Schizophrenia and Huntington’s Disease Neuropathology [J]. Biological Psychiatry Global Open Science, 2023, 3(3): 418-429.

[44] OH Y M, LEE S W, KIM W K, et al. Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy [J]. Nature Neuroscience, 2022, 25(11): 1420-1433.

[45] NANCE M A. Genetic counseling and testing for Huntington's disease: A historical review [J]. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2016, 174(1): 75-92.

[46] FURR STIMMING E, CLAASSEN D O, KAYSON E, et al. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial [J]. The Lancet Neurology, 2023, 22(6): 494-504.

[47] SONG S, SU Z, KON N, et al. ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington's disease [J]. Genes & Development, 2023, 37(5-6): 204-217.

[48] SCHWAB L C, GARAS S N, DROUIN-OUELLET J, et al. Dopamine and Huntington’s disease [J]. Expert Review of Neurotherapeutics, 2015, 15(4): 445-58.

[49] FELDMAN E L, GOUTMAN S A, PETRI S, et al. Amyotrophic lateral sclerosis [J]. The Lancet, 2022, 400 (103 60): 1363-1380.

[50] REETZ K, LISCHEWSKI S A, DOGAN I, et al. Friedreich's ataxia—a rare multisystem disease [J]. The Lancet Neurology, 2025, 24(7): 614-624.