biostudies-literatureXie LShandong Provincial Natural Science FoundationQingdao Science and Technology Benefit People Demonstration Guide Special ProjectNational Natural Science Foundation of ChinaShandong Province Major Scientific and Technical Innovation Project120https://www.ebi.ac.uk/biostudies/studies/S-EPMC12372359biostudies-literatureUnknown15(1)<h4>Background</h4>Spinal cord ischemia reperfusion injury (SCIRI) is a serious disease that can result in irreversible neuronal damage, leading to the loss of sensory and motor function. Cuproptosis, a novel form of regulated cell death, has been studied in various diseases. However, the role and mechanism of cuproptosis in SCIRI remain to be elucidated.<h4>Results</h4>The results of transcriptome analysis showed significant downregulation of ATP7B, which regulates copper ion efflux. Concurrently, another key cuproptosis-related gene, FDX1, was significantly altered. Thus, we performed qPCR and Western blot assays in vivo and in vitro to detect changes in cuproptosis-related genes. The results indicated that cuproptosis was indeed activated by SCIRI or OGD/R. Moreover, immunofluorescence/immunohistochemitry staining and neuronal activity tests were consistent with the above results. Furthermore, we also proved that ammonium tetrathiomolybdate, a copper chelator and cuproptosis inhibitor, could not only ameliorate neuronal damage and promote neuronal survival but also improve lower limb motor dysfunction.<h4>Conclusions</h4>SCIRI caused ATP7B downregulation, which blocked copper ion efflux, leading to copper ion accumulation, DLAT oligomerization, degradation of iron-sulfur cluster proteins and ultimately cuproptosis in neurons.Cell & bioscienceSpinal cord ischemia reperfusion injury induces cuproptosis in neurons.PMC12372359ZR2024QH59022-3-7-smjk-5-nsh824015522021SFGC050282472431Xiao XXie LShi WYu THe QWu HfalseSpinal cord ischemia reperfusion injury induces cuproptosis in neurons.<h4>Background</h4>Spinal cord ischemia reperfusion injury (SCIRI) is a serious disease that can result in irreversible neuronal damage, leading to the loss of sensory and motor function. Cuproptosis, a novel form of regulated cell death, has been studied in various diseases. However, the role and mechanism of cuproptosis in SCIRI remain to be elucidated.<h4>Results</h4>The results of transcriptome analysis showed significant downregulation of ATP7B, which regulates copper ion efflux. Concurrently, another key cuproptosis-related gene, FDX1, was significantly altered. Thus, we performed qPCR and Western blot assays in vivo and in vitro to detect changes in cuproptosis-related genes. The results indicated that cuproptosis was indeed activated by SCIRI or OGD/R. Moreover, immunofluorescence/immunohistochemitry staining and neuronal activity tests were consistent with the above results. Furthermore, we also proved that ammonium tetrathiomolybdate, a copper chelator and cuproptosis inhibitor, could not only ameliorate neuronal damage and promote neuronal survival but also improve lower limb motor dysfunction.<h4>Conclusions</h4>SCIRI caused ATP7B downregulation, which blocked copper ion efflux, leading to copper ion accumulation, DLAT oligomerization, degradation of iron-sulfur cluster proteins and ultimately cuproptosis in neurons.2025-01-01T00:00:00Z2025 Aug2026-06-30T03:23:26.765Z2026-06-30T03:16:15.846ZS-EPMC123723594084196510.1186/s13578-025-01463-1