ATF3 Preserves Macrophage Cholesterol Homeostasis during Metabolic Stress

ATF3 loss in bone marrow-derived macrophages linked to enhanced inflammatory/interferon programs and reduced SREBP2 target gene expression despite elevated cellular cholesterol.

• Why it matters: Macrophages must balance immune activation with sterol homeostasis, but the transcriptional coupling between these programs is not well defined.
• What they did: Compared wild-type and ATF3-deficient macrophages using bulk RNA sequencing after Toll-like receptor stimulation and sterol loading/depletion, measuring cholesterol, cytokines, and sterol-responsive genes; validated relevance with human MASLD datasets and Kupffer cell-specific ATF3 knockout mice.
• The result: ATF3 deficiency preserved sterol-responsive responsiveness yet showed reduced SREBP2-dependent induction and persistent Ch25h upregulation; IFNAR blockade did not normalize Ch25h, while Ch25h reduction partially restored sterol-responsive genes, and Kupffer cell ATF3 deletion increased liver injury and Kupffer cell lipid accumulation.

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