ArticleInflammation research : official journal of the European Histamine Research Society ... [et al.]2026
Agmatine induces mitophagy via the PTS-I2R pathway to increase autophagic flux and attenuate sepsis-induced intestinal epithelial cell apoptosis.
Article in Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe therapeutic options for sepsis-induced intestinal injury, which drives multiple organ dysfunction and mortality, are limited, but the role of polyamine supplements remains unclear. This study aimed to elucidate the protective effect of agmatine (AGM) on sepsis-induced intestinal injury and its mitochondrial-targeted antiapoptotic mechanism in intestinal epithelial cells (IECs).
methodsWe verified the transport and subcellular localization of AGM in IECs via fluorescence assays and established in vitro and in vivo IEC apoptosis models. Functional evaluations using cell viability assays, laser confocal imaging, flow cytometry, transmission electron microscopy, and multiomics techniques were performed.
resultsAGM attenuated sepsis-induced intestinal injury, as evidenced by its ability to lower the serum levels of intestinal damage markers in septic mice, attenuate inflammatory factor production and pathological damage in the intestine, and reduce IEC apoptosis. AGM entered IECs via the polyamine transport system (PTS), but not the NMDA receptor, and inhibited IEC apoptosis induced by TNFα/CHX or TNFα/ActD. Notably, AGM exerted its antiapoptotic effect by targeting the mitochondrial imidazoline I2 receptor (I2R). Mechanistically, AGM induced mitophagy by decreasing the mitochondrial membrane potential without altering mitochondrial number or function, as ROS production, calcium ion influx, ATP generation, and oxygen consumption were unchanged. AGM also increased autophagic flux, as confirmed upon treatment with various autophagy inhibitors.
conclusionAGM alleviates sepsis-induced intestinal injury via the PTS-I2R axis by promoting mitophagy and autophagic flux to inhibit IEC apoptosis, laying a foundation for the use of AGM as a potential nutritional supplement or therapeutic agent for sepsis-induced intestinal injury.
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