Geranylgeranylacetone Alleviates Pulmonary Fibrosis in Mice by Activation of Nrf2 /HO-1/NQO1 Pathway.

Idiopathic pulmonary fibrosis (IPF) carries high mortality with limited treatments. Geranylgeranylacetone (GGA), an HSP70 inducer, exhibits protective effects in lung diseases but remains unexplored in pulmonary fibrosis. This study therefore aimed to assess GGA’s effects on pulmonary fibrosis. Bleomycin (BLM) was used for inducing animal models, and NIH/3T3 fibroblasts were stimulated by TGF-β. HE and Masson’s staining were used for the evaluation of alterations in mouse lung tissues. The molecular testing were assessed with Western blotting, RT-qPCR, and immunofluorescence staining. The results showed that GGA treatment significantly attenuated fibroblast activation and lung fibrosis. Compared to the model group, GGA increased the levels of HSP70, Nrf2, HO-1, NQO1, and GPX4, decreasing the expression of collagen I, α-SMA, NF-κB, IL-6, TNF-α, and ACSL4. However, the Nrf2 inhibitor ML385 partially counteracted this effect. In summary, GGA may partially alleviate oxidative stress, inflammatory response, myofibroblasts activation and ferroptosis by the activation of Nrf2/HO-1/NQO1 signaling pathway, thereby attenuating the progression of pulmonary fibrosis. This suggests that GGA is a promising therapeutic medicine for pulmonary fibrosis.