Dietary Sulfur Amino Acid Sensing and Metabolic Adaptation: From the GCN2–ATF4–FGF21 Axis to Transsulfuration and Redox Homeostasis

Sulfur amino acids (SAAs), mainly methionine and cysteine, play an important role in coordinating nutrient sensing, one-carbon metabolism, redox regulation, and whole-body energy homeostasis. Dietary methionine restriction (MR) and sulfur amino acid restriction (SAAR) have gained increasing interest as nutritional interventions that produce pronounced metabolic benefits in preclinical models, including reductions in adiposity and hepatic lipid accumulation and improvements in insulin sensitivity and glucose regulation. Human intervention studies suggest biological activity and potential metabolic benefit, although the available clinical evidence remains limited and heterogeneous. These effects arise from the coordinated activation of multiple nutrient-responsive pathways. Reduced amino acid availability can stimulate the general control nonderepressible 2–eukaryotic translation initiation factor 2 alpha–activating transcription factor 4 signaling pathway (GCN2–eIF2α–ATF4) integrated stress response, whereas changes in methionine-derived S-adenosylmethionine modulate mechanistic target of rapamycin complex 1 (mTORC1) activity through S-adenosylmethionine sensor upstream of mTORC1 (SAMTOR)-dependent signaling. At the systemic level, hepatic fibroblast growth factor 21 contributes to the regulation of adipose tissue remodeling, energy expenditure, thermogenesis, and insulin sensitivity. At the same time, alterations in transsulfuration reshape cysteine utilization, glutathione metabolism, hydrogen sulfide signaling, and mitochondrial redox adaptation. Importantly, selective MR, broader SAAR, and total protein restriction should not be considered equivalent interventions, as their metabolic effects are influenced by cysteine availability and the degree of restriction. Nevertheless, the translation of these effects to humans remains incompletely established, and available intervention studies are limited in number, duration, and sample size. This review examines the biochemical and molecular mechanisms underlying SAA sensing and metabolic adaptation and evaluates their potential relevance to obesity, type 2 diabetes, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease, with particular emphasis on future applications in precision nutrition.