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Figure 1. Gut microbiota-derived metabolites contribute to endothelial cell dysfunction through multiple pathways. Several metabolites produced by gut microbiota, including indole-3-acetic acid (I3AA), indolepropionic acid (Imp), short-chain fatty acids (SCFAs), bile acids, and trimethylamine N-oxide (TMAO), influence vascular endothelial function. These metabolites can induce endothelial cell dysfunction by promoting ferroptosis and altering cellular homeostasis. TMAO, in particular, activates various signaling pathways involving vascular cell adhesion molecule 1 (VCAM1), protein kinase C (PKC), nuclear factor kappa B (NF-κB), high mobility group box 1 (HMGB1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), lysophosphatidylethanolamine acyltransferase (LPEAT), membrane-bound O-acyltransferase domain-containing 2 (MBOAT2), and succinate dehydrogenase complex iron sulfur subunit B (SDHB). These pathways contribute to increased monocyte adhesion, enhanced endothelial permeability, endothelial-to-mesenchymal transition (EndMT), endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production, and pyroptosis. Additionally, circulating factors such as homocysteine (Hcy), N-acetylneuraminic acid (Neu5Ac), and neutral lipids exacerbate endothelial dysfunction, partly through the solute carrier family 3 member 2 (SLC3A2) transport pathway. Conversely, protective metabolites including β-alanine, carnosine, and acetate may attenuate TMAO-induced endothelial injury. Created using https://BioRender.com.