Zoledronic acid targets the mevalonate pathway causing reduced cell recruitment and attenuation of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreparable scarring of lung tissue, resulting in most patients succumbing rapidly after diagnosis. With limited treatment options available, repurposing of current pharmaceuticals offers an expeditious option to address this dire need. The mevalonate pathway, which is involved in the regulation of cell proliferation, survival and motility, is targeted by the bisphosphonate zoledronic acid (ZA). In this study, administration of ZA reduced myofibroblast transition and blocked NF-kB signaling in macrophages leading to impaired immune cell recruitment. ZA treatment of mice with bleomycin-induced lung damage displayed decreased levels of cytokines in the BALF, plasma, and lung tissue, resulting in less histologically visible fibrotic scarring. Additionally, bleomycin induced production of the ZA target, farnesyl diphosphate synthase (FDPS), was reduced in lung tissue and fibroblasts upon ZA treatment. Therefore, ZA administration offers an expedient and efficacious treatment option against IPF in a clinical setting. TeaserRepurposing of zoledronic acid potentially offers a clinically viable treatment for idiopathic pulmonary fibrosis