Nesfatin-1, a novel energy-regulating peptide, alleviates pulmonary fibrosis by blocking TGF-β1/Smad pathway in an AMPKα-dependent manner

•Nesfatin-1 inhibited bleomycin-induced inflammation and oxidative stress in lung tissues.•Nesfatin-1 suppressed collagen synthesis by blocking TGF-β1/Smad pathway in bleomycin-induced mice.•Nesfatin-1 promoted the phosphorylation of AMPKα in TGF-β1-induced lung fibroblasts.•AMPKα deficiency counteracted Nesfatin-1 -elicited protection against TGF-β1-induced activation of lung fibroblast. Pulmonary fibrosis is a chronic progressive disease which steadily causes a critical public health concern. Nesfatin-1, a novel energy-regulating peptide discovered in 2006, could increase the level of AMPK phosphorylation. Previous studies have unveiled that Nesfatin-1 possessed many pharmacological effects including anti-inflammation, anti-oxidative stress, anti-fibrosis, and the regulation of lipid metabolism. Here, we investigated the impact of Nesfatin-1 on pulmonary fibrosis. Male C57BL/6J mice were intraperitoneally injected with Nesfatin-1 (10 μg·kg−1·day−1) for 21 days since mice were intratracheally administrated with bleomycin (BLM) (2 U/kg). Primary murine lung fibroblasts were stimulated with TGF-β1 (10 ng/ml) for 48 h. The results showed that Nesfatin-1 treatment significantly improved pulmonary function and decreased the production of collagen in BLM-treated mice. Meantime, Nesfatin-1 treatment also inhibited oxidative stress and inflammation in lung tissues from BLM-treated mice. Mechanically, Nesfatin-1 blocked the activation of TGF-β1/Smad2/3 signaling pathway in lung tissues challenged with BLM. In addition, we found that Nesfatin-1 enhanced the phosphorylation of AMPKα during pulmonary fibrosis. However, pharmacological inhibition or genetic deletion of AMPKα could both offset the pulmonary protection mediated by Nesfatin-1 during pulmonary fibrosis. Our experimental results firstly show Nesfatin-1 might serve as a novel treatment or adjuvant against pulmonary fibrosis by blocking TGF-β1/Smad pathway in an AMPKα-dependent manner.