The Emerging Role of N-Lactoyl-Phenylalanine (Lac-Phe) in Metabolic Regulation and Disease: From Exercise-Induced Metabolite to Therapeutic Candidate.

N-Lactoyl-phenylalanine (Lac-Phe), identified in 2022 as an exercise-inducible signaling metabolite, is formed by carnosine dipeptidase 2 via conjugation of lactate and phenylalanine. Its circulating levels rise sharply after intense exercise in mice, humans, and racehorses, reflecting increased glycolytic flux. Beyond exercise, Lac-Phe also rises with feeding and metformin, positioning it as a potential integrator of energy intake, expenditure, and metabolic homeostasis. Centrally, Lac-Phe may contribute to appetite suppression by inhibiting hypothalamic orexigenic agouti-related protein neurons, primarily observed in obese rodent models, while sparing anorexigenic pro-opiomelanocortin neurons, thereby reducing food intake, promoting weight loss, and improving glucose tolerance in obese models without altering energy expenditure. Peripherally, it drives anti-inflammatory M2 macrophage polarization, ameliorating colitis and aiding recovery after spinal cord injury via NF-κB suppression and reactive oxygen species reduction. As a biomarker, Lac-Phe may offer advantages over lactate in reflecting mitochondrial dysfunction in conditions such as MELAS, sepsis, and NADH-reductive stress; however, these observations derive mainly from small-scale or exploratory studies and require prospective validation. Recent studies from 2024 to 2025 further reveal its partial and context-dependent role in mediating metformin's effects, intensity- and sex-dependent responses, renal clearance via SLC17A1/3 transporters, and links to exercise-induced redox adaptations. The first human phase I trial (NCT06743009), launched in 2025, is assessing the metabolic effects of Lac-Phe in obesity. This Perspective summarizes Lac-Phe biosynthesis, physiological mechanisms, including its emerging but largely correlative connections to redox homeostasis, and therapeutic promise, underscoring its potential relevance for exercise-mimicking strategies in metabolic, inflammatory, and redox-related disorders.