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bioRxiv · 10.64898/2026.10.02.756223

PPARγ brakes cytosolic DNA-induced macrophage inflammation by super-enhancer metabolic reprogramming

Meng, P.·Zhang, S.·Fan, X.·Gao, K.·Xu, J.·Zhang, G.·Yuan, Y.·Gao, Q.·Ma, Z.·Yang, F.·Zhang, Y.·Wang, Y.
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Abstract

Cytoplasmic DNA sensing triggers intense innate immune responses that require tight regulation. PPAR{gamma} is a master metabolic regulator in macrophages, but its role in cytoplasmic DNA immunity remains unclear. Using poly(dA:dT) to mimic cytoplasmic DNA stimulation, we combined transcriptomics, epigenomics (PPAR{gamma}/H3K27ac ChIP-seq), and functional assays. Poly(dA:dT) induced a cytokine storm with MAPK activation and apoptosis/necrosis. PPAR{gamma} activation by rosiglitazone (RGZ) antagonized this response, reducing cell death and transcriptionally inhibiting MAPK genes (e.g., DUSP4/10). Mechanistically, PPAR{gamma} bound promoters/enhancers via PPRE motifs and distal intergenic regions, remodeling H3K27ac (reduced at inflammatory loci, increased at metabolic genes). RGZ induced de novo super-enhancers coupling PPAR metabolic programs (e.g., CPT2) with immune suppression by targeting TLR4, CEBPB, and PIM3. Thus, PPAR{gamma} acts as a brake in cytoplasmic DNA immunity, integrating metabolic reprogramming and inflammation suppression through a multi-level genomic/epigenetic program. This study highlights PPAR{gamma} as a key immune-metabolic integrator and therapeutic target for diseases driven by excessive cytoplasmic DNA sensing.

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Meng, P., Zhang, S., Fan, X., Gao, K., Xu, J., Zhang, G., Yuan, Y., Gao, Q., Ma, Z., Yang, F., Zhang, Y., Wang, Y.. 2026-10-08. PPARγ brakes cytosolic DNA-induced macrophage inflammation by super-enhancer metabolic reprogramming. https://doi.org/10.64898/2026.10.02.756223

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