STAT3 controls IL-6-induced epigenomic remodeling and restrains a latent STAT1-associated interferon program in human macrophages.

STAT3 calibrates IL-6–driven epigenomic remodeling in human macrophages, with graded STAT3 chromatin recruitment scaling with H3K27ac deposition and transcription across homeostatic versus inflammatory programs.

• Why it matters: It remains unclear how STAT3 selects among IL-6–linked macrophage outcomes, and whether STAT3 limits alternative STAT1-linked inflammatory programs during cytokine signaling.
• What they did: The study integrated transcriptomic and epigenomic profiling with selective STAT3 degradation in human macrophages, then tested how STAT3 loss reshapes STAT1 recruitment and a delayed amplification loop partially dependent on STING and type I IFN signaling.
• The result: STAT3 degradation permits STAT1 recruitment at a subset of regulatory regions and engages a delayed, STING/type I IFN–partly dependent interferon program; in severe COVID-19, monocytes show exaggerated STAT3 inflammatory signatures with attenuated STAT1 interferon responses.

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