Transcriptional regulation of NK cell state by ELF4 links innate immune licensing to kidney fibrosis

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Fibrosis is a common outcome of chronic tissue injury, yet immune regulators that are conserved across species and translatable to human disease remain poorly defined. By integrating human kidney transcriptomes with multiple murine models of kidney fibrosis, we identified the ETS transcription factor ELF4 as a conserved, immune-enriched regulator associated with disease severity. ELF4 expression was highest in natural killer (NK) cells. Genetic deletion of Elf4 , including NK cell–specific ablation, attenuated experimental kidney injury, with reduced inflammation, fibrosis, and loss of renal function. Single-cell and functional analyses showed that ELF4 deficiency disrupts late-stage NK cell maturation and broadly suppresses cytotoxic and interferon-γ (IFNγ) effector programs. Mechanistically, ELF4 directly sustains STAT1 transcription, maintaining a STAT1–TBX21 program required for NK cell maturation and effector competence. Consistent with this framework, NK cell depletion, IFNγ neutralization, or antisense-mediated suppression of Elf4 phenocopied renal protection. Together, these findings identify ELF4 as a transcriptional licensing factor that links NK cell state to kidney injury and highlight innate immune programming as a potential therapeutic entry point in chronic kidney disease.