Phenylacetylglutamine (PAGln), a metabolite derived from gut bacteria, plays a significant role in health and disease. It is produced from phenylalanine, an amino acid found in dietary sources, through microbial metabolism in the gut. PAGln is involved in the metabolism of phenylacetic acid (PAA) and is conjugated with glutamine and glycine in the liver and kidneys to form PAGln in humans and phenylacetylglycine in rodents. PAGln has been linked to various diseases, including cardiovascular, cerebrovascular, and neurological disorders. It enhances platelet activation through GPCRs and adrenergic receptors, contributing to thrombosis and exacerbating pathological conditions. Elevated levels of PAGln are associated with cardiovascular, cerebrovascular, and neurological diseases. PAGln is also involved in kidney function, with its levels inversely related to plasma levels and more pronounced in patients with normal renal function. PAGln is a biomarker for stroke and is associated with increased risk of stroke recurrence and other cardiovascular events. In neurological disorders, PAGln is linked to Parkinson's disease and multiple sclerosis, with elevated levels associated with disease progression. PAGln is also implicated in other disorders such as sepsis, rheumatoid arthritis, and cystic fibrosis. The review highlights the role of PAGln in disease pathogenesis and its potential as a biomarker and therapeutic target. Further research is needed to fully understand its mechanisms and applications in disease management.Phenylacetylglutamine (PAGln), a metabolite derived from gut bacteria, plays a significant role in health and disease. It is produced from phenylalanine, an amino acid found in dietary sources, through microbial metabolism in the gut. PAGln is involved in the metabolism of phenylacetic acid (PAA) and is conjugated with glutamine and glycine in the liver and kidneys to form PAGln in humans and phenylacetylglycine in rodents. PAGln has been linked to various diseases, including cardiovascular, cerebrovascular, and neurological disorders. It enhances platelet activation through GPCRs and adrenergic receptors, contributing to thrombosis and exacerbating pathological conditions. Elevated levels of PAGln are associated with cardiovascular, cerebrovascular, and neurological diseases. PAGln is also involved in kidney function, with its levels inversely related to plasma levels and more pronounced in patients with normal renal function. PAGln is a biomarker for stroke and is associated with increased risk of stroke recurrence and other cardiovascular events. In neurological disorders, PAGln is linked to Parkinson's disease and multiple sclerosis, with elevated levels associated with disease progression. PAGln is also implicated in other disorders such as sepsis, rheumatoid arthritis, and cystic fibrosis. The review highlights the role of PAGln in disease pathogenesis and its potential as a biomarker and therapeutic target. Further research is needed to fully understand its mechanisms and applications in disease management.