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

Xiaohua Xie; Xiaofeng Wu; Dongsheng Zhao; Ying Liu; Qiyue Du; Yitian Li; Yaping Xu; Yuhang Li; Yan Qiu; Yungang Yang

doi:10.1016/j.phrs.2022.106577

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

Pharmacol Res. 2023 Jan:187:106577. doi: 10.1016/j.phrs.2022.106577. Epub 2022 Nov 23.

Authors

Xiaohua Xie¹, Xiaofeng Wu², Dongsheng Zhao³, Ying Liu⁴, Qiyue Du⁴, Yitian Li⁵, Yaping Xu⁶, Yuhang Li⁷, Yan Qiu⁴, Yungang Yang⁸

Affiliations

¹ Department of Pediatrics, The First Affiliated Hospital of Xiamen University, No.55 Zhenhai Road, Xiamen 361003, China; Institute of Pediatrics, School of Medicine, Xiamen University, No.55 Zhenhai Road, Xiamen 361003, China.
² Department of Pharmacy, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
³ Department of Pharmacy, Quanzhou Medical College, China.
⁴ Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen 361102, China.
⁵ Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen 361102, China; Department of Clinical Pharmacy, The Third Hospital of Mianyang/Sichuan Mental Health Center, Mianyang 621000, Sichuan, China.
⁶ Institute of Respiratory Diseases Xiamen Medical College, Xiamen, Fujian 361002, China; Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian 361002, China.
⁷ CAS Key Laboratory of Design and Assembly of Functional Nanostructures, and Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, China; Xiamen Institute of Rare-earth Materials, Haixi Institutes, Chinese Academy of Sciences, Fujian 361005, China. Electronic address: yuhangli@fjirsm.ac.cn.
⁸ Department of Pediatrics, The First Affiliated Hospital of Xiamen University, No.55 Zhenhai Road, Xiamen 361003, China; Institute of Pediatrics, School of Medicine, Xiamen University, No.55 Zhenhai Road, Xiamen 361003, China. Electronic address: xmyyg@xmu.edu.cn.

PMID: 36435270
DOI: 10.1016/j.phrs.2022.106577

Abstract

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.

Keywords: Bleomycin; Cyclic GMP-AMP synthase (cGAS); Fluvoxamine; Idiopathic pulmonary fibrosis (IPF); Stimulator of interferon genes (STING).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antifibrotic Agents* / therapeutic use
Bleomycin
Fibroblasts / metabolism
Fluvoxamine* / therapeutic use
Idiopathic Pulmonary Fibrosis* / drug therapy
Lung / drug effects
Mice
Nucleotidyltransferases
Transforming Growth Factor beta1 / metabolism

Substances

Bleomycin
Fluvoxamine
Nucleotidyltransferases
Transforming Growth Factor beta1
Antifibrotic Agents