Succinate promotes pulmonary fibrosis through GPR91 and predicts death in idiopathic pulmonary fibrosis

Abstract Background IPF has been associated with a notable disruption of cellular metabolism. It is still unknown how cellular energy metabolism problems contribute to the onset of pulmonary fibrosis. In an effort to pinpoint the metabolic factors that contribute to pulmonary fibrosis, we investigated the serum metabolomic changes among IPF patients. Methods Metabolomics was performed on serum samples from IPF patients using liquid chromatography-mass spectrometry. Further evidence for the crucial metabolic difference came from an IPF cohort. Multivariate analysis and COX regression analysis confirmed its clinical utility in the diagnosis and prognosis of IPF. Our study explored the potential role of this metabolic molecule in pulmonary fibrosis in mice and cells. Results Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF, with succinate being of particular concern. There was an accumulation of serum succinate in a prospective cohort of 55 patients with IPF compared to 19 healthy controls. A high serum succinate level was independently associated with higher rates of disease progression (OR = 13.087, 95% CI (2.819–60.761)) and mortality (HR = 3.418, 95% CI (1.308–8.927)). A succinate accumulation was also observed in mice with lung fibrosis induced by bleomycin (BLM). Exogenous succinate administration exacerbated the lung fibrosis caused by BLM, whereas lowering succinate accumulation lessened the fibrosis. Succinate-specific receptors (GPR91) were also elevated in lung tissues from patients with IPF. Furthermore, GPR91-/- mice were protected against lung fibrosis caused by BLM. Through GPR91, succinate promoted TGF-induced activation of normal human lung fibroblasts in vitro. Conclusions The findings demonstrate a previously unknown and highly novel association between energy metabolic reprogramming, succinate, fibroblast activation, and clinical prognosis in IPF.