Unraveling the role of MiR‐181 in skin fibrosis pathogenesis by targeting NUDT21

Abstract Systemic sclerosis (SSc) is a life‐threatening autoimmune disease characterized by widespread fibrosis in the skin and several internal organs. Nudix Hydrolase 21 (NUDT2 or CFIm25) downregulation in fibroblasts is known to play detrimental roles in both skin and lung fibrosis. This study aims to investigate the upstream mechanisms that lead to NUDT21 repression in skin fibrosis. We identified transforming growth factor β (TGFβ1) as the primary cytokine that downregulated NUDT21 in normal skin fibroblasts. In the bleomycin‐induced dermal fibrosis model, consistent with the peak activation of TGFβ1 at the late fibrotic stage, NUDT21 was downregulated at this stage, and delayed NUDT21 knockdown during this fibrotic phase led to enhanced fibrotic response to bleomycin. Further investigation suggested TGFβ downregulated NUDT21 through microRNA (miRNA) 181a and 181b induction. Both miR‐181a and miR‐181b were elevated in bleomycin‐induced skin fibrosis in mice and primary fibroblasts isolated from SSc patients, and they directly targeted NUDT21 and led to its downregulation in skin fibroblasts. Functional studies demonstrated that miR‐181a and miR‐181b inhibitors attenuated bleomycin‐induced skin fibrosis in mice in association with decreased NUDT21 expression, while miR‐181a and miR‐181b mimics promoted bleomycin‐induced fibrosis. Overall, these findings suggest a novel role for miR‐181a/b in SSc pathogenesis by repressing NUDT21 expression.