A novel LncRNA TUG1/miR-30d/e-3p/SNAI2 ceRNA axis drives dermal fibrosis in systemic sclerosis via direct transcriptional activation of COL1A1.

Abstract

Systemic sclerosis (SSc) is a severe autoimmune disease characterized by progressive dermal fibrosis, aberrant fibroblast activation, and excessive collagen deposition. Although noncoding RNA-mediated regulation has been increasingly implicated in fibrotic diseases, the role of the long noncoding RNA taurine-upregulated gene 1 (TUG1) in SSc-associated skin fibrosis remains unclear. In this study, we investigated the function and mechanism of TUG1 in primary dermal fibroblasts isolated from lesional skin of patients with SSc and in a bleomycin-induced mouse model of dermal fibrosis. TUG1 expression was significantly increased in SSc dermal fibroblasts. Functional assays showed that TUG1 promoted fibroblast proliferation, migration, and COL1A1 expression, whereas TUG1 silencing attenuated these profibrotic phenotypes. Mechanistically, TUG1 acted as a competing endogenous RNA by sponging miR-30d-3p and miR-30e-3p, thereby relieving their repression of the transcription factor SNAI2. SNAI2 directly bound to the COL1A1 promoter and activated its transcription. In vivo, Tug1 knockdown alleviated bleomycin-induced dermal fibrosis, increased miR-30d-3p/miR-30e-3p levels, and reduced SNAI2 expression and collagen deposition. These findings identify the TUG1-miR-30d-3p/miR-30e-3p-SNAI2-COL1A1 axis as a potential therapeutic target in SSc skin fibrosis.