Phenylalanine homeostasis in metabolic disorders: epidemiological trends, pathophysiological mechanisms, and clinical...

Metabolic diseases, characterized by dysregulated energy homeostasis, represent a major global health challenge. While research has traditionally focused on glucose and lipid metabolism, emerging metabolomic and epidemiological evidence implicates circulating amino acid imbalances as a key factor for metabolic diseases. Phenylalanine (Phe) is an essential aromatic amino acid primarily metabolized by hepatic phenylalanine hydroxylase. Epidemiological investigation demonstrates that elevated plasma Phe is a significant risk factor for obesity, type 2 diabetes mellitus (T2DM) and cancer. Mechanistically, phenylalanyl-tRNA synthetase mediates phenylalanylation of insulin receptor β, subsequently inhibiting insulin signal transduction. Meanwhile, Phe and its catabolites (e.g., phenylpyruvate) impair mitochondrial function, induce oxidative stress, and inflammation, ultimately lead to insulin resistance and hepatic steatosis. Interestingly, the derivatives of Phe(such as exercise-induced N-lactoylphenylalanine) can suppress appetite and improve glucose homeostasis, suggesting functional diversity in the Phe metabolic network. In addition, clinical therapeutic strategies are gradually transitioning from traditional strict dietary restriction to personalized and multimodal interventions including nutrition, pharmacology and enzyme replacement therapy. However, ensuring the continuity, efficacy and safety of the treatment strategy remains a formidable challenge. In conclusion, this review explores the pathophysiological impact of Phe by integrating the epidemiological and molecular evidence for its role in metabolic diseases. From a translational medicine perspective, we further evaluate current therapeutic strategies, aiming to promote the clinical translation of Phe metabolism.