Creatine regulating neuronal ferroptosis by reducing STAT1-SOCS1 signaling activation in Alzheimer’s disease model mice

doi:10.16098/j.issn.0529-1356.2025.03.001

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Acta Anatomica Sinica ›› 2025, Vol. 56 ›› Issue (3) : 253-259. DOI: 10.16098/j.issn.0529-1356.2025.03.001

Neurobiology

Creatine regulating neuronal ferroptosis by reducing STAT1-SOCS1 signaling activation in Alzheimer’s disease model mice

SHAO Xiang-qi WANG Xue WANG Tao YUAN Bo QIU Wen-ying LIU Fan* MA Chao*

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Abstract

Objective To explore whether creatine therapy regulates neuronal ferroptosis by inhibiting the activation of STAT1 signaling pathway associated with suppressor of cytokine signaling 1 (SOCS1) in Alzheimer’s disease. Methods Immunohistochemical staining and counting of positive results using paraffin sections of human brain frontal lobes were employed to determine the trend of changes in the target proteins. Further validation was performed by immunofluorescence and Western blotting. STAT1 phosphorylation was inhibited by creatine injection using eleven FAD4Tmice and by cerebellar medullary pool puncture, and the expression of target proteins was examined by immunohistochemistry and immunofluorescence after postmortem sampling. Results Compared with the age controls, interferon-γ (IFN-γ), an activating cytokine of the STAT1 signaling pathway, and SOCS1, a negative regulator of STAT1 activation, were both significantly up-regulated, STAT1 phosphorylation was enhanced, and the ferroptosis markers ferritin light chain (FTL) and cystine/glutamate transporter(xCT) increased markedly in the cortex of AD human brains; Creatine treatment of FAD4Tmice resulted in a reduction of both IFN-γ and SOCS1, and a significant decrease in the ferroptosis markers FTL and xCT (SLC7A11). Conclusion Creatine ameliorates neuronal ferroptosis in AD model mice by reducing neuronal STAT1SOCS1 signalling activation.

Key words

Interferon-γ

/ Suppressor of cytokine signaling 1 / Ferroptosis / Ferritin light chain / Cystine/glutamate transporter / Alzheimer’s disease / Mouse

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SHAO Xiang-qi WANG Xue WANG Tao YUAN Bo QIU Wen-ying LIU Fan MA Chao. Creatine regulating neuronal ferroptosis by reducing STAT1-SOCS1 signaling activation in Alzheimer’s disease model mice[J]. Acta Anatomica Sinica. 2025, 56(3): 253-259 https://doi.org/10.16098/j.issn.0529-1356.2025.03.001

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