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

Area of Science:

• Pharmacology
• Pulmonary Medicine
• Immunology

Background:

• Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options.
• Current therapies for IPF have shown modest efficacy, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To investigate the potential anti-fibrotic effects of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), in the context of IPF.
• To elucidate the molecular mechanisms underlying fluvoxamine's therapeutic activity in pulmonary fibrosis.

Main Methods:

• In vitro studies assessing fibroblast activation and migration upon TGF-β1 challenge.
• In vivo experiments using bleomycin (BLM)-induced lung fibrosis model in mice.
• Assessment of pulmonary function, inflammatory markers, and extracellular matrix production.

Main Results:

• Fluvoxamine inhibited cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) signaling pathways.
• It attenuated fibroblast activation and migration by modulating downstream targets like PERK/eIF2α and TBK1/YAP.
• Fluvoxamine dose-dependently improved lung function, reduced inflammation, and decreased extracellular matrix deposition in a BLM-induced lung fibrosis mouse model.
• Efficacy was comparable to pirfenidone (PFD) at a 10 mg/kg dose of fluvoxamine versus 30 mg/kg of PFD.

Conclusions:

• Fluvoxamine demonstrates significant anti-fibrotic properties against pulmonary fibrosis.
• The drug acts by inhibiting cGAS-STING and related downstream signaling pathways involved in fibroblast activation.
• Fluvoxamine represents a promising therapeutic candidate for treating idiopathic pulmonary fibrosis.