Ganetespib as an inhibitor of heat shock protein 90 alleviates pulmonary fibrosis by inhibiting the Wnt/β-catenin signaling pathway

Pulmonary fibrosis, a progressive interstitial lung disease with rising global incidence, currently has limited therapeutic options. Ganetespib is a potent HSP90 Inhibitor, has shown anti-fibrotic potential in liver models, but its mechanism in pulmonary fibrosis remains unclear. In this study, we demonstrated that Ganetespib significantly suppressed HSP90 expression in vitro and in vivo and attenuated fibroblast-myofibroblast transformation. In vivo experiments, utilizing protein expression analysis, mRNA, immunofluorescence, and histopathology elucidated Ganetespib reduced nuclear translocation of β-catenin and decreased expression of downstream targets c-Myc and attenuated BLM-induced pulmonary fibrosis. Mechanistically, we demonstrated through in vitro experiments that Ganetespib. inhibited the transformation of fibroblasts to myofibroblasts by inhibiting Wnt/β-catenin signaling, regulated redox homeostasis and inflammatory responses, and delayed the progression of pulmonary fibrosis. Overall, these results suggest that inhibition of HSP90 expression alleviates pulmonary fibrosis in vitro and in vivo. Therefore, HSP90 may be a potential strategy for the treatment of pulmonary fibrosis.

FMT; Ganetespib; HSP90; Pulmonary fibrosis.