The processes underlying synchronous multiple organ
fibrosis in
systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in
nicotinamide adenine dinucleotide (
NAD+) that is due to dysregulation of NAD+ homeostasis and involves the
NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular
fibrosis signatures, as well as clinical
fibrosis scores, while expression of key
NAD+-synthesizing
enzymes is unaltered. Boosting NAD+ via genetic or pharmacological CD38 targeting or NAD+ precursor supplementation protected mice from skin, lung, and
peritoneal fibrosis. In mechanistic experiments, CD38 was found to reduce NAD+ levels and
sirtuin activity to augment cellular fibrotic responses, while inhibiting CD38 had the opposite effect. Thus, we identify CD38 upregulation and resulting disrupted NAD+ homeostasis as a fundamental mechanism driving
fibrosis in SSc, suggesting that CD38 might represent a novel therapeutic target.