The tryptophan metabolite indole 3-propionic acid alleviates lung ischemia–reperfusion injury via prostaglandin reductase 2 in male mice

Lung ischemia/reperfusion injury (LI/R) is a common complication post-cardiothoracic surgery, primarily driven by inflammation and oxidative stress. Tryptophan and its metabolites play a critical role in various pathophysiological processes, including the inflammatory response and oxidative stress. This study aims to investigates their therapeutic potential against LI/R injury. Dietary supplementation with tryptophan significantly alleviated lung injury induced by LI/R, while tryptophan-free diet (TFD) aggravates LI/R Injury. Quantification of tryptophan and its major metabolites in serum revealed an opposite regulatory trend of indole 3-propionic acid (IPA) in mice serum with tryptophan supplementation and TFD. Further experiments demonstrated that IPA exerted a protective effect on pulmonary epithelial cells against hypoxic damage in a dose-dependent manner in vitro and in vivo. Proteomic profiling identified prostaglandin reductase 2 (PTGR2) as potential targets of IPA. Overexpression of PTGR2 reverses the protective effects of IPA treatment on mice LI/R injury. Mechanistically, IPA suppressed PTGR2 expression, thereby increased NRF2 levels in the cell nucleus modulating the transcription and expression of antioxidant genes such as Sod2, and Gpx1. These findings suggest that IPA, a metabolite of tryptophan, mitigate LI/R injury by suppressing PTGR2 expression, thereby increasing NRF2 levels in the cell nucleus. This study provides a novel therapeutic strategy for alleviating LI/R injury in male mice.