IL-33 as a component of neutrophil extracellular traps mediates contrast-induced acute kidney injury by promoting ferroptosis in tubular epithelial cells

作者：Ma M, Zhang H, Deng W, Du X, Chen T, Wang Z, Chen C, Chen M, Pan B, Chen D, Sun Q, Lu M, Li Y, Tang R, Qiu Z, Wan X, Cao C · 发表于：Kidney international · 年份：2026 · DOI：10.1016/j.kint.2026.06.039

INTRODUCTION: Contrast-induced acute kidney injury (CIAKI) is a leading cause of hospital-acquired kidney dysfunction, yet its immune-mediated pathogenic mechanisms remain poorly defined. Neutrophil extracellular traps (NETs) have been implicated in acute kidney injury. However, whether contrast agents directly induce NETs formation and whether NETs drive tubular ferroptosis through IL-33 has not been investigated. METHODS: A prospective cohort of 330 patients undergoing coronary angiography was enrolled, with serial measurement of circulating NETs markers (myeloperoxidase, neutrophil elastase) and IL-33 at pre-contrast, two- and 12-hour time points. A murine CIAKI model was established in wild-type, peptidyl arginine deaminase 4 (PAD4) -knockout, and IL-33-knockout mice, and single-cell transcriptomic profiling of CIAKI kidneys was performed. In vitro, the serine/threonine kinase IKKα- and β-catenin-overexpressing and knockdown HK-2 cells were stimulated with iodixanol-induced NETs to evaluate how NETs regulate ferroptosis through IL-33-mediated modulation of IKKα and β-catenin. RESULTS: CIAKI occurred in 12.1% (40/330) of patients. Circulating NETs markers and IL-33 were significantly elevated at two and 12 hours post-contrast in CIAKI compared with non-CIAKI patients. Single-cell transcriptomics identified neutrophils as the predominant source of IL-33 in CIAKI kidneys and revealed enrichment of NET formation and ferroptosis pathways. In vivo, PAD4 and IL-33 deficiency e...