Splicing factor SRSF6 mediates pleural fibrosis

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Molecular Biology

Background:

• Pleural fibrosis, characterized by excessive extracellular matrix deposition, impairs lung function and is linked to conditions like tuberculous pleurisy.
• Pleural mesothelial cells (PMCs) are central to fibrosis, but the underlying molecular mechanisms require further elucidation.
• The role of the RNA-binding splicing factor SRSF6 in pleural fibrosis pathogenesis is currently unknown.

Purpose of the Study:

• To investigate the role and mechanism of SRSF6 in the development of pleural fibrosis.
• To determine if SRSF6 levels are altered in patients with tuberculous pleural effusions (TBPE).
• To evaluate SRSF6 inhibition as a potential therapeutic strategy for pleural fibrosis.

Main Methods:

• Quantified SRSF6 levels in patient-derived TBPE cells and human PMCs treated with fibrotic stimuli (decellularized TBPE, bleomycin, TGF-β1).
• Assessed SRSF6's in vitro effects on PMC proliferation and collagen synthesis (COL1A2).
• Evaluated the in vivo efficacy of SRSF6 inhibition in a mouse model of experimental pleural fibrosis.

Main Results:

• SRSF6 protein levels were elevated in cells from TBPE and increased in PMCs upon exposure to fibrotic agents.
• SRSF6 promoted PMC proliferation and COL1A2 synthesis in vitro.
• SRSF6 inhibition effectively ameliorated experimental pleural fibrosis in mice.
• SRSF6 upregulation correlated with SMAD2/3 activation, SOX4 increase, and miRNA-506-3p decrease in PMCs.

Conclusions:

• SRSF6 plays a critical role in inducing pleural fibrosis through pathways involving WNT5A and SMAD1/5/9 signaling.
• SRSF6 promotes pleural fibrosis by enhancing PMC proliferation and fibrotic matrix production.
• Targeting SRSF6 presents a promising therapeutic avenue for managing pleural fibrosis.