Noncoding RNA TY1 reverses fibrosis in systemic sclerosis by attenuating the cGAS/STING pathway

DNA damage and the cGAS/STING innate immunity pathway have been associated with fibrosis in systemic sclerosis (SSc), but a cause-and-effect role has not been established. Here we report the effects of TY1, a noncoding RNA drug of the exomer class that suppresses DNA damage and thereby inhibits cGAS/STING, in human SSc cells and in 2 preclinical models of SSc. Macrophages from patients with SSc exhibited high levels of phosphorylated DNA damage, cGAS, 2'3'-cGAMP, STING, and IFNs, all of which decreased after exposure to TY1. In mice that had been injected s.c. with bleomycin to model SSc, exercise tolerance, cardiac function, lung hydroxyproline, and skin thickness reverted to normal levels after oral administration of TY1. Similar therapeutic benefits were evident in the genetic tsk-1 mouse model of SSc. TY1 attenuated fibrosis and/or fibrotic gene expression in both mouse models of SSc and in human SSc skin fibroblasts. Our findings support the hypothesis that cGAS/STING, activated by DNA damage, is a key driver of fibrosis in SSc.