Intercellular GAS6-AXL signaling triggers podocyte cuproptosis in acute kidney injury upstream regulated by CEBPD
- 1Department of Nephrology, The First People’s Hospital of Nanning, Nanning, China
Abstract
This study aims to investigate the role of cuproptosis, a novel form of regulated cell death, in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Multi-omics approaches, including single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and in vitro experiments based on cells, were integrated to dissect the spatiotemporal regulation of cuproptosis in AKI. Podocytes exhibited the highest cuproptosis activity. A critical intercellular communication axis was identified, wherein endothelial cell-derived GAS6 signals through the podocyte receptors AXL/TYRO3. The transcription factor CEBPD was upregulated early in AKI and was found to positively regulate the GAS6-related pathway, with its target genes enriched in TGF-β and JAK-STAT signaling, ultimately leading to receptor activation and cuproptosis. Spatially, CEBPD activation preceded the increase in AXL, followed by late-phase upregulation of GAS6. The alteration in AXL protein expression was confirmed in vitro.Our study reveals a CEBPD-mediated transcriptional program that drives podocyte cuproptosis by transactivating the AXL receptor, providing novel mechanistic insights into the AKI-to-CKD transition.
Related
- Genome instability triggers intercellular DNA transfer between human cells
- Ceruloplasmin deficiency promotes osteoclast cuproptosis-like cell death and is associated with higher bone mass in OVX mice with coordinated activation of AMPK/p53 signaling
- Butyrate Triggers Neuronal Signaling via Release of Colonic Serotonin in a Microfluidic Model of Gut-Brain Axis
- Natural killer cell-derived extracellular vesicles in cancer: mediators of intercellular communication and tumor immune signaling
- Folic acid polyglutamylation triggers MAP2K5 signaling to induce adipocyte lipid catabolism
BibTeX
@article{liang2026intercellular,
title = {{Intercellular GAS6-AXL signaling triggers podocyte cuproptosis in acute kidney injury upstream regulated by CEBPD}},
author = {Jingmei Liang and Yuyun Hu and Bing Liao},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0359878},
url = {https://doi.org/10.1371/journal.pone.0359878},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Intercellular GAS6-AXL signaling triggers podocyte cuproptosis in acute kidney injury upstream regulated by CEBPD
AU - Jingmei Liang
AU - Yuyun Hu
AU - Bing Liao
PY - 2026
DA - 2026/10/09
JO - PLOS One
DO - 10.1371/journal.pone.0359878
UR - https://doi.org/10.1371/journal.pone.0359878
AB - This study aims to investigate the role of cuproptosis, a novel form of regulated cell death, in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Multi-omics approaches, including single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and in vitro experiments based on cells, were integrated to dissect the spatiotemporal regulation of cuproptosis in AKI. Podocytes exhibited the highest cuproptosis activity. A critical intercellular communication axis was identified, wherein endothelial cell-derived GAS6 signals through the podocyte receptors AXL/TYRO3. The transcription factor CEBPD was upregulated early in AKI and was found to positively regulate the GAS6-related pathway, with its target genes enriched in TGF-β and JAK-STAT signaling, ultimately leading to receptor activation and cuproptosis. Spatially, CEBPD activation preceded the increase in AXL, followed by late-phase upregulation of GAS6. The alteration in AXL protein expression was confirmed in vitro.Our study reveals a CEBPD-mediated transcriptional program that drives podocyte cuproptosis by transactivating the AXL receptor, providing novel mechanistic insights into the AKI-to-CKD transition.
SN - 1932-6203
ER -