Desaminotyrosine Alleviates Hepatic Ischemia-Reperfusion Injury via the MAPK/Ferroptosis Axis and Bifidobacterium pseudolongum Modulation.

Abstract

Ischemia-reperfusion (I/R) is a common and unavoidable phenomenon during surgeries such as hepatectomy and liver transplantation, severely affecting patient prognosis. However, clinically intervention and treatment measures remain very limited. Using human hepatocyte organoid hypoxia-reoxygenation (H/R) and murine hepatic ischemia-reperfusion (I/R) models, we demonstrate that the microbiota-derived flavonoid desaminotyrosine (DAT) attenuates I/R-induced hepatic injury by suppressing inflammation and apoptosis while promoting the abundance of probiotic Bifidobacterium in the gut. Through integrated spatial transcriptomics and metabolomics, we identified that DAT specifically alters the MAPK signaling pathway/ ferroptosis gene transcriptome in the portal vein (PV) zones, promotes the production of antioxidants (taurine) in the central vein (CV) zones, reduces the level of pro-ferritinosis substrates (arachidonic acid), thereby enhancing the expression of GPX4 and Nrf2, inhibiting ferroptosis, then ameliorate hepatic I/R injury. Meanwhile, the pseudo-germ-free mouse model confirmed that DAT alleviated hepatic I/R injury in a gut microbiota dependent manner. DAT reduces hepatic I/R injury by increasing the abundance of gut Bifidobacterium pseudolongum (Bif). Our research results reveal a novel microbial metabolite that improves hepatic I/R injury, clarify the inhibitory effect of DAT on ferroptosis, discover new therapeutic uses of DAT, and identify Bif as a potential novel probiotic for preventing liver I/R injury, providing new options for the preventive treatment of liver I/R injury.