A metabolic “switch” that could help reset scar-producing cells in scleroderma

Researchers at University of Michigan Health and collaborating institutions have identified a metabolic enzyme that may offer a fundamentally new way to attack one of the most difficult-to-treat features of systemic sclerosis, or scleroderma: progressive and potentially life threatening tissue scarring.

Despite decades of research and numerous clinical trials, effective treatment of scleroderma fibrosis remains a major unmet need.

Currently available therapies have limited ability to produce durable control of the fibrosis that can damage the skin, lungs and other internal organs.

In a new study published in the Journal of Investigative Dermatology, investigators identify nicotinamide N-methyltransferase, or NNMT, as a key regulator of the abnormal metabolic and epigenetic programming that can keep fibroblasts “locked” into a persistently activated, scar-producing state.

The researchers tested a novel small-molecule NNMT inhibitor in fibroblasts from patients with systemic sclerosis and in a mouse model of skin fibrosis.

Inhibiting NNMT suppressed the transformation of fibroblasts into scar-producing myofibroblasts and reduced excessive production of collagen and other extracellular matrix components.

Importantly, NNMT inhibition also corrected metabolic abnormalities associated with the fibrotic state, including alterations in NAD⁺ homeostasis and cellular methylation balance.

In mice, inhibitor treatment reduced pathological skin thickening and collagen accumulation, preventing loss of the normal fat layer beneath the skin.

The study suggests a potentially important shift in how fibrosis might be treated.

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Rather than simply blocking one of the many signals that stimulate collagen production, targeting NNMT may help “reset” the fibrotic cell itself by correcting the abnormal metabolic and epigenetic program that sustains its scar-producing behavior.

“Fibroblasts in scleroderma acquire a kind of cellular memory that keeps them producing scar tissue even when the original stimulus is no longer present,” said senior author John Varga, M.D., Chief of Rheumatology at U-M Health.

“Our findings suggest that targeting NNMT activity provides a way to reset that cellular memory—restoring a more normal metabolic and epigenetic state rather than simply blocking an individual fibrotic signal.”

The study establishes NNMT as a previously underappreciated connection between cellular metabolism, epigenetic regulation and fibrosis.

SEE ALSO: For scleroderma research, patients seen as essential co-creators

The findings also raise the possibility that NNMT and its associated metabolic signature could eventually help researchers better define or stage fibrotic disease and identify patients most likely to benefit from targeted treatment.

“Ultimately, the work opens an exciting new avenue toward therapies designed not simply to slow scar formation, but potentially to reprogram the cells responsible for fibrosis toward a healthier state,” said Varga.

“Further research will be needed to determine whether NNMT inhibition can be translated safely and effectively into treatment for people with systemic sclerosis and other fibrotic diseases.”

Additional authors: Kamal Saba, Sunny Kataria, Umesh Kumar, Prihanka Verma, John Keyokgy, Gabriel Walters, Pei-Suen Tsou and M Astif Amin from the Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA. Bo Shi from the Department of Dermatology, Northwestern University, Chicago, IL USA. Claudia C S Chini and Eduardo N Chini from the Metabolism and Molecular Nutrition Laboratory, Kogod Center on Aging, Department of Anaesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Jacksonville, FL, USA. Tianqi Zhao and Rong Huang from the Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN USA. Iredia D Iyamu from the Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN USA and the Department of Medicinal Chemistry, University of Kansas, Lawrence, KS USA.

Paper cited: “A Bisubstrate Inhibitor of NNMT Suppresses Myofibroblast Reprogramming to Mitigate Skin Fibrosis,” Journal of Investigative Dermatology. DOI: 10.1016/j.jid.2026.07.037

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