Targeting CD38-Dependent NAD+ Metabolism to Mitigate Multiple Organ Fibrosis

Synchronous fibrosis in multiple organs is the defining hallmark of systemic sclerosis (SSc), but underlying mechanisms remain poorly understood. Organismal decline in nicotinamide adenine dinucleotide (NAD+), the sole substrate for enzymes critical for cellular metabolism, is implicated in age-related pathologies, and is due to NAD+ consumption catalyzed by CD38. We now show that CD38 is upregulated in SSc skin biopsies, and its levels associate with molecular fibrosis signatures as well as clinical skin fibrosis scores, while key NAD+ -synthesizing enzyme levels are unaltered. Boosting NAD+ via CD38 targeting or by NAD+ precursor supplementation protected older mice from skin and lung fibrosis. Mechanistically, CD38 reduced NAD+ levels and sirtuin activity to augment fibrotic responses, while inhibition of CD38 had the opposite effect. Thus we identify upregulation of CD38 and resulting disrupted NAD+ homeostasis as a fundamental pathogenic mechanism driving fibrosis in SSc, suggesting that CD38 might represent a target for therapy.