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bioRxiv · 10.64898/2026.04.27.721223

Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling

Zhou, Y.·Li, K.·Xie, Y.·Li, Z.·Yang, Y.·Qiao, P.·Liu, W.·Bai, Y.·Xue, K.·Gudjonsson, J.·Wang, G.·Shao, S.
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Abstract

Chronic skin inflammation frequently recurs at the same anatomical sites after therapy withdrawal, implying stromal cells may encode local inflammatory memory. Here, we identified nicotinamide N-methyltransferase (NNMT) as a central metabolic-epigenetic regulator of fibroblast inflammatory memory enabling psoriasis relapse. Single-cell and spatial transcriptomics revealed that dermal fibroblasts acquire a persistent senescence-associated secretory phenotype (SASP) during inflammation, maintaining pro-inflammatory niche in resolved skin that supports CD 8+CD 103+ tissue-resident memory T cell (Trm) differentiation. Multi-omics profiling demonstrated that NNMT depletes S-adenosylmethionine (SAM), reduces H 3K 27me3 deposition, and permits sustained AP-1 occupancy at SASP gene promoters. Fibroblast-specific NNMT ablation or pharmacologic inhibition suppressed SASP activity, limited Trm accumulation, and prevented both initiation and relapse of skin inflammation in mice. These findings establish NNMT as a stromal regulator linking fibroblast metabolism to durable epigenetic memory and propose its targeting to erase inflammatory memory and achieve long-term remission in psoriasis and related immune-mediated diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/721223v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@34b2f4org.highwire.dtl.DTLVardef@1d0bb89org.highwire.dtl.DTLVardef@c8277borg.highwire.dtl.DTLVardef@9825ac_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic Abstract:C_FLOATNO Proposed mechanism through which NNMT-driven fibroblast SASP facilitates the initiation and recurrence of psoriasis C_FIG

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Zhou, Y., Li, K., Xie, Y., Li, Z., Yang, Y., Qiao, P., Liu, W., Bai, Y., Xue, K., Gudjonsson, J., Wang, G., Shao, S.. 2026-04-30. Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling. https://doi.org/10.64898/2026.04.27.721223

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