Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis

Area of Science:

• Cell Biology
• Pulmonary Medicine
• Metabolomics

Background:

• Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by alveolar destruction and fibrosis.
• Altered levels of metabolites, including succinate, are observed in IPF patients.
• Fibroblasts play a central role in IPF pathogenesis.

Purpose of the Study:

• To investigate the role of succinate and its receptor, succinate receptor 1 (SUCNR1), in lung fibrosis.
• To determine the effects of succinate on fibroblast behavior and fibrotic marker expression.
• To evaluate the therapeutic potential of targeting the succinate/SUCNR1 axis.

Main Methods:

• SUCNR1 expression analysis using Western blots, qPCR, and in situ hybridization.
• In vitro studies with IPF and normal human lung fibroblasts (NHLF) treated with succinate.
• In vivo studies using a bleomycin-induced mouse model of pulmonary fibrosis.

Main Results:

• SUCNR1 is expressed in various lung cells, including fibroblasts.
• Succinate treatment increased fibrosis markers (e.g., alpha-smooth muscle actin, collagen) and fibroblast-to-myofibroblast transition in IPF fibroblasts.
• In vivo, succinate exacerbated lung collagen accumulation and weight loss in mice.
• SUCNR1 knockdown or ERK inhibition abolished succinate-induced profibrotic effects.

Conclusions:

• Succinate and SUCNR1 signaling promote profibrotic changes in lung fibroblasts both in vitro and in vivo.
• The succinate/SUCNR1 axis represents a potential therapeutic target for IPF treatment.