{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:02:55Z","timestamp":1790870575720,"version":"4.1.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sepsis-associated acute kidney injury is a critical condition driven by immune dysregulation, particularly involving neutrophils, yet their heterogeneity and molecular contributions remain underexplored. This study employed a multi-omics approach, integrating single-cell and bulk RNA sequencing from 21 sepsis samples and Escherichia coli-induced sepsis datasets, alongside bioinformatics, machine learning, and experimental validation in a rat model and human peripheral blood. We identified four neutrophil subtypes\u2014pro-inflammatory, anti-inflammatory, mature, and immature\u2014revealing a significant increase in pro-inflammatory neutrophils in sepsis (40.53% versus 4.19% in controls) and a decrease in anti-inflammatory neutrophils (18.43% versus 27.04%). Four hub genes, peptidyl arginine deiminase 4, caspase 4, complement receptor 1, and mitogen-activated protein kinase 14, were pinpointed as key drivers, with peptidyl arginine deiminase 4 mediating neutrophil extracellular trap formation and exacerbating renal damage. In a rat model, peptidyl arginine deiminase 4 knockdown reduced trap formation and alleviated kidney injury (p-value less than 0.01). Human samples confirmed elevated gene expression in sepsis (p-value less than 0.05). These findings highlight neutrophil heterogeneity and molecular mechanisms in sepsis, with potential implications for sepsis-associated acute kidney injury (SAKI), proposing novel biomarkers and therapeutic targets for precision medicine.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1637692","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T05:31:24Z","timestamp":1759383084000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi-omics analysis reveals neutrophil heterogeneity and key molecular drivers in sepsis-associated acute kidney 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