Fluvoxamine alleviates bleomycin-induced lung fibrosis via regulating the cGAS-STING pathway

• DOI: 10.1016/j.phrs.2022.106577
• Publication Date: 2022-11-23T19:15:50Z
• Authors: Xiaohua Xie; Xiaofeng Wu; Dongsheng Zhao; Ying Liu; Qiyue Du; Yitian Li; Yaping Xu; Yuhang Li; Yan Qiu; Yungang Yang
• Keywords: 0303 health sciences; Fibroblasts; Nucleotidyltransferases; Idiopathic Pulmonary Fibrosis; 3. Good health; Transforming Growth Factor beta1; Mice; Bleomycin; 03 medical and health sciences; Fluvoxamine; Animals; Antifibrotic Agents; Lung

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with high mortality and limited effective therapy. Herein, we reported that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), used in depression and anxiety treatment, also exhibited therapeutic activities in IPF. Fluvoxamine inhibited cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), restrained the activation of their downstream targets, including PERK/ eIF2α/ c-Myc/ miR-9-5p/ TBPL1 and TBK1/ YAP/ JNK1/2/ Bnip3/ CaMKII/ cofilin signaling, thus attenuated the activation and migration of fibroblasts upon TGF-β1 challenge. Fluvoxamine dose-dependently improved pulmonary function, decreased the expression of inflammatory factors, reduced excessive production of extracellular matrix, and thus alleviated bleomycin (BLM)-induced lung fibrosis in mice. Moreover, fluvoxamine at a dose of 10 mg/ kg showed similar efficacy as pirfenidone (PFD) at a dose of 30 mg/kg in a mice model of lung fibrosis. In summary, our results suggest that fluvoxamine is an effective anti-fibrotic agent for IPF.