Copanlisib ameliorates pulmonary fibrosis by modulating cellular autophagy through PI3K/Akt/mTORC1 pathway

Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic interstitial lung disease (ILD), has a poor prognosis, and effective drugs, including nintedanib and pirfenidone, are limited. Therefore, developing new drugs for treating pulmonary fibrosis is of the highest priority. The inhibition of cellular autophagy in lung fibroblasts is an important mechanism involved in pulmonary fibrosis, and the PI3K/Akt/mTORC1 pathway is responsible for modulating the level of intracellular autophagy. As a result, copanlisib, a pan-class I PI3K inhibitor, has promise for preventing pulmonary fibrosis by ameliorating cellular autophagy. This study aimed to evaluate the effect and underlying mechanism of copanlisib in pulmonary fibrosis.

In this study, we evaluated the antifibrotic effect of copanlisib by using a mouse model of bleomycin (BLM)-induced pulmonary fibrosis for in vivo experiments and mouse lung fibroblasts (Mlg cells) for in vitro experiments.

As a result, copanlisib markedly alleviated BLM-induced collagen deposition and improved pulmonary function and ventilation volume in vivo. In addition, both in vivo and in vitro experiments verified that copanlisib showed a dose-dependent association with reduced fibrotic activity and changes in autophagy markers consistent with increased activity. These effects were accompanied by the reduced phosphorylation of PI3K, Akt, and mTORC1, suggesting a potential mechanistic link between PI3K/mTOR inhibition and the observed therapeutic efficacy in these experimental settings.

In conclusion, copanlisib is a promising candidate as a treatment for pulmonary fibrosis.