Repurposing flavopiridol as an inhaled therapeutic for pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with limited therapeutic options. Cyclin-dependent kinase 9 (CDK9), a key transcriptional regulator, has been implicated in fibrotic diseases, but no therapies targeting CDK9 have been developed for IPF. This investigation found that CDK9 expression was significantly elevated in IPF lung fibroblasts, correlating with an enhanced fibrogenic transcriptional profile and phenotype. Treatment with our designated CDK9 inhibitor, flavopiridol, exhibited significant anti-fibrotic effects, including suppression of fibrotic marker expression, reduction of fibroblast invasion and proliferation in vitro, and inhibition of fibroblastic lesion expansion in precision-cut lung slices ex vivo. In a bleomycin-induced mouse model of lung fibrosis, systemic administration of flavopiridol improved survival, attenuated body weight loss, and reduced fibrotic lesions and collagen deposition, outperforming the FDA-approved drug nintedanib. Further, we developed an inhalable formulation of flavopiridol and demonstrated its efficacy in mitigating fibrosis through local lung delivery, which minimized systemic drug exposure and potential adverse effects. These findings establish CDK9 as a critical regulator of lung fibrosis and provide compelling evidence for developing CDK9 inhibitors as novel therapeutic agents for IPF.