Anlotinib Alleviates Pulmonary Fibrosis by Inhibiting PFKFB3-Driven Glycolysis via the Downregulation of PCBP3

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the normal alveolar network is gradually replaced by fibrotic scars. Current evidence implicates the differentiation of fibroblasts into myofibroblasts is correlated with metabolic alterations in IPF. Here, we tried to decipher whether anlotinib, a novel multitargeted tyrosine kinase inhibitor, could alleviate bleomycin (BLM) induced pulmonary fibrosis and explore the possible mechanisms. Methods: In this study, C57BL/6 mice were intraperitoneally injected with anlotinib immediately or 7 days after BLM injection to investigate the preventative and therapeutic effects of anlotinib on BLM-induced pulmonary fibrosis. Additionally, we used primary mouse lung fibroblasts and the IMR90 cell line to examine the effects and the mechanism of anlotinib on fibroblasts. Findings: We observed that anlotinib limited BLM-induced lung fibrosis and inhibited the lactate accumulation in mice. Meanwhile, we found that anlotinib could inhibit the PFKFB3-dependent glycolysis in fibroblasts and diminish myofibroblasts differentiation. The mechanism by which anlotinib exerts potent antifibrotic effects was by downregulating the RNA binding protein (RBP) PCBP3, decreasing PFKFB3 translation and inhibiting glycolysis in fibroblasts. Interpretation: Our data suggest that anlotinib has antifibrotic effects on the lungs and provide a possible mechanism. Anlotinib may be a novel and potent candidate for protection against pulmonary fibrosis. We also identify PCBP3 that is involved in the regulation of glycolysis reprogramming and lung fibrogenesis, which could be a potential therapeutic target for pulmonary fibrosis. Fund: This work was supported by National Natural Science Foundation of China (No. 81870058). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: All experiments were conducted in accordance with protocols approved by the Southern Medical University Institutional Animal Care and Use Committee.