Intercellular GAS6-AXL signaling triggers podocyte cuproptosis in acute kidney injury upstream regulated by CEBPD

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.