Therapeutic Potential of Flavopiridol in the Suppression of Lung Fibrosis Via CDK9 Inhibition: American Journal of Respiratory and Critical Care Medicine

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with limited therapeutic options. Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional regulation and is associated with the pathogenesis of fibrotic diseases. Notwithstanding substantial evidence that connects CDK9 to organ fibrosis, there remain no effective therapeutic agents specifically designed to target CDK9 to mitigate pulmonary fibrosis or arrest its advancement. METHODS: We investigated CDK9 expression in lung fibroblasts from IPF patients using single-cell RNA sequencing, followed by protein analysis through Western blotting. The CDK9 inhibitor flavopiridol was evaluated in vitro using IPF lung fibroblast cell lines and in vivo in a bleomycin-induced murine model of IPF. We assessed the antifibrotic effects of flavopiridol, comparing systemic and localized pulmonary delivery through histological examination and quantification of fibrotic markers. RESULTS: Elevated CDK9 expression was observed in IPF lung fibroblasts, correlating with fibrogenic gene expression profiles. In vitro cell-based assays demonstrated that CDK9 inhibition by flavopiridol reduced the expression of fibrotic markers, as well as fibroblast cell invasion and proliferation. In a mouse model of lung fibrosis, systemic administration of flavopiridol attenuated body weight loss, improved survival rates, and reduced fibrotic lesions and collagen deposition, showing superior antifibrotic efficacy compared to the FDA-approved drug nintedanib. Notably, targeted pulmonary delivery of inhaled flavopiridol further decreased fibrotic lesions and lung inflammation, allowing direct drug targeting to affected lung tissues, rapid therapeutic action, and reduced systemic side effects. CONCLUSION: Our findings suggest that CDK9 serves as a critical regulator of fibrogenesis in IPF and that inhibiting CDK9 through the use of flavopiridol represents a promising therapeutic strategy. The formulation of a novel method for the pulmonary delivery of flavopiridol presents a potential targeted treatment approach for IPF.