Background Pulmonary fibrosis is a chronic progressive fibrotic interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition caused by activated fibroblasts. Increasing evidence shows that matrix stiffness is essential in promoting fibroblast activation and profibrotic changes. Here, we investigated the expression and function of matrix stiffness-regulated ZNF416 in pulmonary fibrotic lung fibroblasts. Methods 1 kappa (soft), 60 kappa (stiff) gel-coated coverslips, or transforming growth factor-beta 1 (TGF-β1)-cultured lung fibroblasts and the gain- or loss- of the ZNF416 function assays were performed in vitro. We also established two experimental pulmonary fibrosis mouse models by a single intratracheal instillation with 50 mg/kg silica or 6 mg/kg bleomycin (BLM). ZNF416 siRNA-loaded liposomes and TGF-β1 receptor inhibitor SB431542 were administrated in vivo. Results Our study identified that ZNF416 could regulate fibroblast differentiation, proliferation, and contraction by promoting the nuclear accumulation of p-Smad2/3. Besides, ZNF416 siRNA-loaded liposome delivery by tail-vein could passively target the fibrotic area in the lung, and co-administration of ZNF416 siRNA-loaded liposomes and SB431542 significantly protects mice against silica or BLM-induced lung injury and fibrosis. Conclusion In this study, our results indicate that mechanosensitive ZNF416 is a potential molecular target for the treatment of pulmonary fibrosis. Strategies aimed at silencing ZNF416 could be a promising approach to fight against pulmonary fibrosis.

Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function leading to a fatal outcome. As an essential epigenetic regulator of DNA methylation, the involvement of Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in fibroblast activation remains largely undefined in pulmonary fibrosis. In the present study, we found that growth factor-β1(TGF-β1)-mediated upregulation of UHRF1 repressed Beclin1 via its promoter methylation induction which finally results in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated Beclin 1 in lung fibroblasts. Henceforth, intravenous administration of UHRF1 siRNA-loaded liposomes significantly protected mice against experimental pulmonary fibrosis.Accordingly, our data suggested that UHRF1 might be a novel potential therapeutic target in the pathogenesis of pulmonary fibrosis.

Background Silicosis is a global occupational lung disease caused by the accumulation of silica dust. There is a lack of effective clinical drugs, and the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms by which IL33 involves in silicosis progression need further exploration. Results Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin (BLM) and silica treatment. ChIP assay, knockdown and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or co-cultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. Also, Treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. Conclusions In this study, we identified that NPM1 could involve in the progression of silicosis, which was regulated by IL33/ERK/AP-1 signaling. And treatment methods targeting this pathway may provide new anti-fibrotic clues in pulmonary fibrosis.

Background: Silicosis is a global occupational lung disease caused by the accumulation of silica dust. There is a lack of effective clinical drugs, and the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms by which IL33 involves in silicosis progression need further exploration. Results: Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin (BLM) and silica treatment. ChIP assay, knockdown and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or co-cultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. Also, Treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. Conclusions: In this study, we identified that NPM1 could involve in the progression of silicosis, which was regulated by IL33/ERK/AP-1 signaling. And treatment methods targeting this pathway may provide new anti-fibrotic clues in pulmonary fibrosis.

Silicosis is a global occupational pulmonary disease due to the accumulation of silica dust in the lung. Lacking effective clinical drugs makes the treatment of this disease quite challenging in clinics largely because the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms governing the involvement of IL33 in silicosis progression remain to be further explored. Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin (BLM) and silica treatment. Chromatin immunoprecipitation (ChIP) assay, knockdown, and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or co-cultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. And more, treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. In conclusion, the involvement of NPM1 in the progression of silicosis is regulated by the IL33/ERK/AP-1 signaling axis, which is the potential therapeutic target candidate in developing novel anti-fibrotic strategies for pulmonary fibrosis.