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

作者：Yijun He, Yuanyuan Han, Lijun Zou, Tingting Yao, Yan Zhang, Xin Lv, Mao Jiang, Lingzhi Long, Mengyu Li, Xiaoyun Cheng, Guoliang Jiang, Zhangzhe Peng, Lijian Tao, Jie Meng, Wei Xie · 发表于：Scientific Reports · 年份：2024 · DOI：10.1038/s41598-024-64844-5 · 被引用次数：19 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Inhalation and Respiratory Drug Delivery、Chronic Obstructive Pulmonary Disease (COPD) Research

Idiopathic pulmonary fibrosis (IPF) is believed to be associated with a notable disruption of cellular energy metabolism. By detecting the changes of energy metabolites in the serum of patients with pulmonary fibrosis, we aimed to investigate the diagnostic and prognostic value of energy metabolites in IPF, and further elucidated the mechanism of their involvement in pulmonary fibrosis. Through metabolomics research, it was discovered that the TCA cycle intermediates changed dramatically in IPF patients. In another validation cohort of 55 patients with IPF compared to 19 healthy controls, it was found that succinate, an intermediate product of TCA cycle, has diagnostic and prognostic value in IPF. The cut-off levels of serum succinate were 98.36 μM for distinguishing IPF from healthy controls (sensitivity, 83.64%; specificity, 63.16%; likelihood ratio, 2.27, respectively). Moreover, 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)). In addition, accumulation of succinate and increased expression of the succinate receptor GPR91 were found in both IPF patients and BLM mouse models of pulmonary fibrosis. Reducing succinate accumulation in BLM mice alleviated pulmonary fibrosis and 21d mortality, while exogenous administration of succinate can aggravate pulmonary fibrosis in BLM mice. Furthermore, GPR91 deficiency protected against lung fibrosis caused...