Schisandrin B attenuates ischemic acute kidney injury in a CTR1-dependent manner by inhibiting cuproptosis
- 1Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University (FangDa Hospital) , ,
- 2Guangyuan Lizhou Secondary Specialized School , , ,
- 3Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University , ,
Abstract
Background
Acute kidney injury (AKI) remains a global health challenge with high mortality rates and no targeted pharmacotherapy. Although regulated cell death (RCD) drives renal tubular epithelial cell (RTEC) injury, the involvement of cuproptosis, a copper-triggered RCD characterized by lipoylated protein aggregation and iron-sulfur cluster loss, remains unexplored in acute kidney injury (AKI).Methods
Integrated single-cell transcriptomics (GSE180420), a human renal biopsy cohort (n = 22), ischemia-reperfusion (I/R) mouse models, and hypoxia-reoxygenation (H/R) cellular models were used to characterize cuproptosis. Multi-omics profiling, molecular docking, and CTR1 (encoded by SLC31A1)-specific siRNA knockdown were used to explore the mechanism of action of Schisandrin B (SchB).Results
Single-cell RNA sequencing of murine ischemia-reperfusion (I/R) kidneys revealed that cuproptosis was a predominant RCD modality, accounting for approximately one-third of all regulated cell death events in renal tubular epithelial cells (RTECs). This finding was corroborated in human AKI biopsies and in murine I/R kidneys, where the key cuproptosis proteins ferredoxin 1 (FDX1) and copper transporter 1 (CTR1) were markedly upregulated, accompanied by significant copper accumulation and tubule injury. Under the tested conditions, SchB exhibited protective effects at least comparable to those of the classical copper chelator tetrathiomolybdate (TTM) in attenuating copper-dependent cytotoxicity in vitro. SchB-regulated differentially expressed genes were significantly enriched in glutathione metabolism, p53 signaling, cellular senescence, and PI3K-Akt pathways. Molecular docking predicted a direct interaction between SchB and CTR1 (binding energy -5.1 kcal/mol)siRNA-mediated depletion of CTR1 partially abolished the protective effects of SchB against copper-induced RTEC death, indicating that CTR1 may be required, at least in part, for SchB-induced cytoprotection in RTECs.Conclusion
This study identifies cuproptosis as a predominant and previously unrecognized RCD pathway in ischemic AKI. SchB inhibits cuproptosis in a CTR1-dependent manner. These findings provide a preclinical rationale for further investigation of this natural product as a potential therapeutic candidate for ischemic kidney disease.
Related
- Breviscapine attenuates myocardial ischemia-reperfusion injury by inhibiting ferroptosis via activation of NRF2/SLC7A11/GPX4 pathway
- Artesunate attenuates inflammation and neurological impairment in intracerebral hemorrhage mice by inhibiting microglia NLRP3/ASC/Caspase-1
- Ginsenoside Rh2, a putative functional modulator of Annexin A2, attenuates post-hemorrhagic stroke cerebral edema via inhibiting vesicular transcytosis
- miR-7a-5p attenuates hypoxic-ischemic encephalopathy by suppressing PARP1-mediated parthanatos
- Huaier Attenuates Renal Injury in Type 2 Diabetic Nephropathy by Ameliorating Mitochondrial Dysfunction and Inhibiting Tubular Epithelial Cell Apoptosis.
BibTeX
@article{lin2026schisandrin,
title = {{Schisandrin B attenuates ischemic acute kidney injury in a CTR1-dependent manner by inhibiting cuproptosis}},
author = {Lirong Lin and Shahong He and Xujia Yang and Luquan Zheng and Wei Tan and Ke Li and Jurong Yang},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1993380},
url = {https://europepmc.org/article/PMC/PMC13716859},
note = {CC BY},
}
RIS
TY - JOUR
TI - Schisandrin B attenuates ischemic acute kidney injury in a CTR1-dependent manner by inhibiting cuproptosis
AU - Lirong Lin
AU - Shahong He
AU - Xujia Yang
AU - Luquan Zheng
AU - Wei Tan
AU - Ke Li
AU - Jurong Yang
PY - 2026
DA - 2026/10/15
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1993380
UR - https://europepmc.org/article/PMC/PMC13716859
AB - Background Acute kidney injury (AKI) remains a global health challenge with high mortality rates and no targeted pharmacotherapy. Although regulated cell death (RCD) drives renal tubular epithelial cell (RTEC) injury, the involvement of cuproptosis, a copper-triggered RCD characterized by lipoylated protein aggregation and iron-sulfur cluster loss, remains unexplored in acute kidney injury (AKI).Methods Integrated single-cell transcriptomics (GSE180420), a human renal biopsy cohort (n = 22), ischemia-reperfusion (I/R) mouse models, and hypoxia-reoxygenation (H/R) cellular models were used to characterize cuproptosis. Multi-omics profiling, molecular docking, and CTR1 (encoded by SLC31A1)-specific siRNA knockdown were used to explore the mechanism of action of Schisandrin B (SchB).Results Single-cell RNA sequencing of murine ischemia-reperfusion (I/R) kidneys revealed that cuproptosis was a predominant RCD modality, accounting for approximately one-third of all regulated cell death events in renal tubular epithelial cells (RTECs). This finding was corroborated in human AKI biopsies and in murine I/R kidneys, where the key cuproptosis proteins ferredoxin 1 (FDX1) and copper transporter 1 (CTR1) were markedly upregulated, accompanied by significant copper accumulation and tubule injury. Under the tested conditions, SchB exhibited protective effects at least comparable to those of the classical copper chelator tetrathiomolybdate (TTM) in attenuating copper-dependent cytotoxicity in vitro. SchB-regulated differentially expressed genes were significantly enriched in glutathione metabolism, p53 signaling, cellular senescence, and PI3K-Akt pathways. Molecular docking predicted a direct interaction between SchB and CTR1 (binding energy -5.1 kcal/mol)siRNA-mediated depletion of CTR1 partially abolished the protective effects of SchB against copper-induced RTEC death, indicating that CTR1 may be required, at least in part, for SchB-induced cytoprotection in RTECs.Conclusion This study identifies cuproptosis as a predominant and previously unrecognized RCD pathway in ischemic AKI. SchB inhibits cuproptosis in a CTR1-dependent manner. These findings provide a preclinical rationale for further investigation of this natural product as a potential therapeutic candidate for ischemic kidney disease.
SN - 2296-634X
ER -