Targeting Nicotinamide N-Methyltransferase: A Novel Approach to Mitigate Fibroblast Activation and Skin Fibrosis in Systemic Sclerosis

Highlight

• NNMT expression is significantly elevated in dermal fibroblasts within systemic sclerosis (SSc) skin lesions, especially in myofibroblast subsets driving fibrosis.
• Silencing or pharmacologic inhibition of NNMT disrupts methylation balance via altering SAM/SAH ratio and histone methylation, suppressing profibrotic gene programs induced by TGFβ.
• NNMT modulates a transcriptional regulatory network involving ATF4, SOX9, and SRF which promotes extracellular matrix gene expression and collagen synthesis.
• Inhibition of NNMT ameliorates bleomycin-induced skin fibrosis in preclinical models, positing NNMT as a promising therapeutic target in SSc.

Study Background and Disease Burden