Dysregulation of SRSF3/circSAMD4/CIRBP Axis Promotes Iodinated Contrast-induced Acute Kidney Injury

Iodinated contrast agents are a common cause of contrast-induced acute kidney injury (CI-AKI), yet the underlying mechanisms remain unclear. We found that circSAMD4 is markedly upregulated in renal tubular epithelial cells (RTECs) from iohexol-induced CI-AKI mice and patients diagnosed with acute tubular injury (ATI). Silencing circSAMD4 alleviated kidney injury and tubular cell death in CI-AKI mice, whereas its overexpression promoted apoptosis in iohexol-treated RTECs. Mechanistically, circSAMD4 binds to cold-inducible RNA-binding protein (CIRBP) and inhibits its nuclear import. Renal tubule-specific Cirbp deletion mitigated CI-AKI, while CIRBP overexpression abolished the protective effects of circSAMD4 knockdown against iohexol-induced apoptosis. CircSAMD4 upregulation in iohexol-treated RTECs was driven by serine/arginine-rich splicing factor 3 (SRSF3) downregulation. Similar molecular alterations in clinical samples correlated with kidney function decline. These findings identify the SRSF3/circSAMD4/CIRBP axis as a novel pathogenic mechanism in CI-AKI and highlight circSAMD4 as a promising therapeutic target.