Pulmonary fibrosis (PF) is a progressive and often fatal interstitial lung disease characterized by persistent fibroblast activation, excessive extracellular matrix deposition and irreversible destruction of lung architecture. Although the angiotensin-(1–7) [Ang-(1–7)]/Mas axis is increasingly recognized as a protective branch of the renin–angiotensin system, its role in pulmonary fibrosis and the underlying redox-related mechanisms remain insufficiently understood. This study aimed to determine whether activation of the Ang-(1–7)/Mas axis attenuates pulmonary fibrosis and to explore whether its effects are mediated through regulation of Nox4–Nrf2 redox homeostasis.

Antifibrotic effects were evaluated in both in vitro and in vivo models. TGF-β1-stimulated HFL-1 and NIH-3T3 cells were used to assess fibroblast-to-myofibroblast transition after treatment with Ang-(1–7), with or without the Mas receptor antagonist A779. A bleomycin-induced pulmonary fibrosis mouse model was established and treated with Ang-(1–7), A779 or the Mas receptor agonist AVE0991. Fibrosis was assessed by histopathology, hydroxyproline assay, immunofluorescence, qRT–PCR and western blotting. Inflammatory cytokines and oxidative stress markers were measured in cells, serum and bronchoalveolar lavage fluid. Key molecules involved in redox regulation, including Nox4, p62, Keap1, Nrf2, HO-1 and NQO1, were further examined.

Ang-(1–7) markedly inhibited TGF-β1-induced fibroblast activation, reducing α-SMA, collagen I and collagen III expression in vitro. In bleomycin-treated mice, Ang-(1–7) alleviated weight loss, improved survival, reduced inflammatory infiltration and collagen deposition, and ameliorated overall fibrotic injury. These effects were accompanied by decreased levels of TGF-β1, TNF-α and IL-6, increased IL-10, reduced ROS and MDA accumulation, and restored antioxidant enzyme activity. Mechanistically, Ang-(1–7) downregulated Nox4, increased p62 expression, suppressed Keap1, promoted Nrf2 nuclear translocation, and enhanced HO-1 and NQO1 expression. AVE0991 reproduced, whereas A779 largely reversed, these protective effects.

Activation of the Ang-(1–7)/Mas axis exerts potent antifibrotic, anti-inflammatory and antioxidant effects in pulmonary fibrosis, at least in part through restoration of Nox4–Nrf2 redox balance. These findings identify the Ang-(1–7)/Mas pathway as a promising therapeutic target for fibrotic lung disease.