(Vienna, 06 November 2026) A research team at the Medical University of Vienna has identified a molecular mechanism that plays an important role in the development of skin fibrosis in systemic sclerosis. This rare autoimmune disease causes progressive thickening and hardening of the skin and can also affect internal organs. The researchers demonstrated that the metabolic enzyme nicotinamide N-methyltransferase (NNMT) plays a key role in the abnormal activation of connective tissue cells. Targeted inhibition of the enzyme reduced skin fibrosis in preclinical models. The findings, recently published in the journal Annals of the Rheumatic Diseases, open up new perspectives for the development of targeted therapies.
The study was led by Thomas Karonitsch from the Division of Rheumatology at the Department of Medicine III of MedUni Vienna, with Anela Tosevska as first author. Researchers from the Department of Dermatology also contributed to the study. The team combined molecular analyses with experiments involving human skin cells and preclinical disease models to investigate the mechanisms underlying abnormal connective tissue accumulation.
Systemic sclerosis is characterised by excessive production of collagen and other components of connective tissue. This process is driven by fibroblasts, which remain persistently activated and cause progressive thickening and hardening of the tissue. The molecular processes responsible for maintaining this sustained activation are not yet fully understood. “We wanted to understand what keeps fibroblasts in this persistently activated state,” explains first author Anela Tosevska. “Our findings identify NNMT as an important regulator and reveal how changes in cellular metabolism can directly influence the development of fibrosis.”
Link between cellular metabolism and fibrosis identified
By analysing gene expression data from skin samples obtained from patients with systemic sclerosis, the researchers found that NNMT expression was elevated in affected skin. This was particularly pronounced in fibroblast populations that contribute substantially to the development of fibrosis. Higher NNMT expression was also associated with more severe skin involvement.
Further experiments revealed how the enzyme links cellular metabolism to the regulation of genes involved in fibroblast activation. The researchers identified gene programmes regulated by several transcription factors, including ATF4, SOX9 and SRF. When NNMT expression was specifically suppressed in human fibroblasts, collagen production, cell migration and other fibrosis-associated processes decreased. These findings were also confirmed in fibroblasts obtained from patients with systemic sclerosis.
Targeted enzyme inhibition reduces skin fibrosis
Building on these findings, the researchers investigated whether NNMT could serve as a therapeutic target. Using a selective inhibitor of the enzyme, they were able to suppress fibrosis-associated molecular processes in human fibroblasts. NNMT inhibition also proved effective in an experimental mouse model, reducing the accumulation of activated fibroblasts and attenuating skin fibrosis.
“The fact that pharmacological inhibition of NNMT reduced fibrosis in our experimental model is particularly encouraging,” says senior author Thomas Karonitsch. “While further research is needed before these findings can be translated into clinical treatments, they provide a promising starting point for developing new therapeutic approaches.”
The study was conducted in close collaboration between the Division of Rheumatology and the Department of Dermatology at MedUni Vienna. In particular, the research group led by Beate Lichtenberger and the contribution of Peter Maximilian Heil helped integrate clinical and experimental approaches.
Treating systemic sclerosis remains a major medical challenge, particularly when progressive fibrosis has already caused irreversible tissue damage. By identifying NNMT as an important regulator of fibroblast activation, the study provides new insights into the mechanisms underlying the disease and establishes a scientific basis for the development of targeted treatment strategies. Further studies will be needed to determine whether inhibition of the enzyme can also be used safely and effectively in patients.
Publication: Annals of the Rheumatic Diseases
Nicotinamide N-Methyltransferase drives fibroblast activation and skin fibrosis in systemic sclerosis
Anela Tosevska, Karolina von Dalwigk, Shaohua Zhu, Jiajia Pang, Lisa Gröbl, Ece Danisman, Felix Kartnig, Ana Korosec, Birgit Niederreiter, Lukas Kremp, Carl-Walter Steiner, Juan Manuel Sacnun, Stephan Blüml, Thomas Köcher, Daniel Aletaha, Hans P. Kiener, Leonhard X. Heinz, Peter Heil, Beate M. Lichtenberger, Thomas Karonitsch.
Annals of the Rheumatic Diseases (2026)
DOI: https://doi.org/10.1016/j.ard.2026.10.3163