Metabolic reprogramming is a central feature of many human diseases, and therapies that target altered metabolic dependencies are moving from concept to clinical testing. Amino acid homeostasis links essential and nonessential amino acid supply with branched-chain amino acid (BCAA) catabolism, one-carbon metabolism, mechanistic target of rapamycin complex 1 (mTORC1)/general control nonderepressible 2 (GCN2) nutrient sensing, glutathione-dependent redox control, epigenetic regulation, and the gut microbiota-amino acid axis. When this network is disturbed, amino acid flux can contribute to disease initiation and progression rather than simply mirroring established pathology. This review synthesizes how amino acid metabolism supports the nervous, cardiovascular, digestive, metabolic-endocrine, immune, skeletal, urinary and reproductive systems, as well as malignant and inherited metabolic disorders. We also examine how pathway-level disturbances converge on excitotoxicity, endothelial dysfunction, insulin resistance, inflammation, fibrosis, immune escape, toxic metabolite accumulation, and impaired fertility. Rather than catalog isolated findings, we emphasize unifying principles and unresolved controversies, including the context-dependent effects of BCAA signaling, the causal versus biomarker status of circulating amino acid signatures, host-gut microbiome crosstalk, and the therapeutic window of dietary, enzymatic, transporter-targeted, and microbiota-based interventions. Finally, we assess clinical translation, drawing lessons from late-stage trial failures and emerging strategies with realistic potential for precision metabolic therapy.
