Systemic sclerosis & Raynaud's
Nicotinamide N-methyltransferase drives fibroblast activation and skin fibrosis in systemic sclerosis
Authors' conclusion
These findings identify a TGFβ-NNMT-ATF4/SOX9/SRF regulatory network linking metabolic regulation to DF activation. Targeting NNMT may represent a therapeutic strategy to attenuate fibrosis in SSc.
Study context
- Population
- SSc skin datasets and primary human dermal fibroblasts; bleomycin-induced dermal fibrosis model
- Outcome
- NNMT expression in SSc skin
Methodological detailsSmall interfering RNA (siRNA)-mediated Nicotinamide N-methyltransferase (NNMT) knockdown or pharmacological NNMT inhibition in primary human dermal fibroblast (DFs), QuantSeq 3' RNA-Seq following ATF4, SOX9 and serum response factor (SRF) knockdown, bleomycin-induced dermal fibrosis
- siRNA-mediated NNMT knockdown or pharmacological NNMT inhibition in primary human DFs
- QuantSeq 3' RNA-Seq following ATF4, SOX9 and SRF knockdown
- Bleomycin-induced dermal fibrosis
Main finding
As reported in the abstract
- NNMT was upregulated in SSc skin across independent cohorts and enriched in disease-expanded myofibroblast states
Further findings
Effects of NNMT knockdown
- NNMT knockdown altered the S-adenosylmethionine (SAM)/S-adenosylhomocysteine ratio and histone methylation patterns, and attenuated TGFβ-induced profibrotic programs
Mechanism
- NNMT supported TGFβ-induced activation of an ATF4/SOX9/SRF transcriptional network that contributed to extracellular matrix (ECM) gene expression and collagen secretion
Pharmacological NNMT inhibition
- Recapitulated key effects of NNMT depletion, suppressed disease-associated SSc fibroblast programs, and attenuated experimental dermal fibrosis in vivo
Original publication
Nicotinamide N-methyltransferase drives fibroblast activation and skin fibrosis in systemic sclerosis. Ann Rheum Dis. Published 2 November 2026. doi:10.
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