{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:41:57Z","timestamp":1785426117834,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council, Taiwan","award":["111-2320-B-002-016-MY3"],"award-info":[{"award-number":["111-2320-B-002-016-MY3"]}]},{"name":"National Science and Technology Council, Taiwan","award":["112-2320-B-005-002"],"award-info":[{"award-number":["112-2320-B-005-002"]}]},{"name":"National Science and Technology Council, Taiwan","award":["113-2320-B-005-009"],"award-info":[{"award-number":["113-2320-B-005-009"]}]},{"name":"National Science and Technology Council, Taiwan","award":["114-2320-B-005-010"],"award-info":[{"award-number":["114-2320-B-005-010"]}]},{"name":"National Science and Technology Council, Taiwan","award":["114-2320-B-002-047-MY3"],"award-info":[{"award-number":["114-2320-B-002-047-MY3"]}]},{"award":["111-2320-B-002-016-MY3"],"award-info":[{"award-number":["111-2320-B-002-016-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["112-2320-B-005-002"],"award-info":[{"award-number":["112-2320-B-005-002"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["113-2320-B-005-009"],"award-info":[{"award-number":["113-2320-B-005-009"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["114-2320-B-005-010"],"award-info":[{"award-number":["114-2320-B-005-010"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["114-2320-B-002-047-MY3"],"award-info":[{"award-number":["114-2320-B-002-047-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Taiwan University Hospital Research Program","award":["NTUH.113-UN0028"],"award-info":[{"award-number":["NTUH.113-UN0028"]}]},{"award":["NTUH.113-UN0028"],"award-info":[{"award-number":["NTUH.113-UN0028"]}],"id":[{"id":"https:\/\/ror.org\/03nteze27","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Collaborative Research Projects of the National Taiwan University College of Medicine, National Taiwan University Hospital, and Min-Sheng General Hospital","award":["109F005-112-E"],"award-info":[{"award-number":["109F005-112-E"]}]},{"name":"Collaborative Research Projects of the National Taiwan University College of Medicine, National Taiwan University Hospital, and Min-Sheng General Hospital","award":["109F-005-113-C"],"award-info":[{"award-number":["109F-005-113-C"]}]},{"name":"Collaborative Research Projects of the National Taiwan University College of Medicine, National Taiwan University Hospital, and Min-Sheng General Hospital","award":["109F-005-114-C"],"award-info":[{"award-number":["109F-005-114-C"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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-\u03baB 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/antiox15040441","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T07:57:55Z","timestamp":1775116675000},"page":"441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Emerging Role of N-Lactoyl-Phenylalanine (Lac-Phe) in Metabolic Regulation and Disease: From Exercise-Induced Metabolite to Therapeutic Candidate"],"prefix":"10.3390","volume":"15","author":[{"given":"Julia Chu-Ning","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, 145, Xingda Road, South District, Taichung 402202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, 1, Jenai Road Section 1, Zhongzheng District, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1546-6877","authenticated-orcid":false,"given":"Ming-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, 1, Jenai Road Section 1, Zhongzheng District, Taipei 100233, Taiwan"},{"name":"Department of Isotope Application Research, National Atomic Research Institute, 1000, Wenhua Road, Longtan District, Taoyuan 325207, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, 1, Jenai Road Section 1, Zhongzheng District, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9593-4062","authenticated-orcid":false,"given":"Tzong-Shyuan","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, 1, Jenai Road Section 1, Zhongzheng District, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/s41586-022-04828-5","article-title":"An exercise-inducible metabolite that suppresses feeding and obesity","volume":"606","author":"Li","year":"2022","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hoene, M., Zhao, X., Machann, J., Birkenfeld, A.L., Heni, M., Peter, A., Niess, A., Moller, A., Lehmann, R., and Xu, G. (2022). Exercise-induced N-lactoylphenylalanine predicts adipose tissue loss during endurance training in overweight and obese humans. Metabolites, 13.","DOI":"10.3390\/metabo13010015"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.tem.2024.05.007","article-title":"Lac-Phe (N-lactoyl-phenylalanine)","volume":"35","author":"Xiao","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1038\/s42255-025-01377-9","article-title":"Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice","volume":"7","author":"Liu","year":"2025","journal-title":"Nat. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s42255-024-01018-7","article-title":"Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans","volume":"6","author":"Scott","year":"2024","journal-title":"Nat. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6601","DOI":"10.1073\/pnas.1424638112","article-title":"N-lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids","volume":"112","author":"Jansen","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/s42255-024-00999-9","article-title":"Lac-Phe mediates the effects of metformin on food intake and body weight","volume":"6","author":"Xiao","year":"2024","journal-title":"Nat. Metab."},{"key":"ref_8","unstructured":"University of Aarhus (2025, May 13). The Metabolic Effects of the Exercise-Metabolite N-Lactoyl-phenylalanine (Lac-Phe). ClinicalTrials.gov Identifier: NCT06743009, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06743009."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Hedaya, L., Naja, K., Almuraikhy, S., Anwardeen, N., Elashi, A.A., Al-Asmakh, M., Zughaier, S.M., Espino-Guarch, M., Aldirbashi, O.Y., and Davey, G.P. (2025). N-Lactoyl phenylalanine disrupts insulin signaling, induces inflammation, and impairs mitochondrial respiration in cell models. Cells, 14.","DOI":"10.3390\/cells14161296"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41419-019-2036-9","article-title":"Mitochondrial 3243A > G mutation confers pro-atherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells","volume":"10","author":"Pek","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s11306-024-02089-z","article-title":"Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock","volume":"20","author":"Rogers","year":"2024","journal-title":"Metabolomics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e136055","DOI":"10.1172\/JCI136055","article-title":"Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity","volume":"131","author":"Sharma","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"172","DOI":"10.4103\/AGINGADV.AGINGADV-D-24-00011","article-title":"N-lactoyl phenylalanine suppresses appetite and obesity with important implications for aging and age-related diseases","volume":"1","author":"Hinton","year":"2024","journal-title":"Aging Adv."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/s12974-025-03495-3","article-title":"N-Lactoyl-Phenylalanine modulates lipid metabolism in microglia\/macrophage via the AMPK-PGC1\u03b1-PPAR\u03b3 pathway to promote recovery in mice with spinal cord injury","volume":"22","author":"Ying","year":"2025","journal-title":"J. Neuroinflamm."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jermei, J., Jiao, H., Shiba, A., Goedhart, J.C., Tandari, R., Kalsbeek, A., Struys, E.A., and Yi, C.X. (2025). High-calorie diet consumption induces Lac-Phe changes in the brain in a time-of-day manner independent of exercise. Metabolites, 15.","DOI":"10.3390\/metabo15060375"},{"key":"ref_16","first-page":"1225","article-title":"Metformin as the first line antidiabetic agent","volume":"56","author":"Svacina","year":"2010","journal-title":"Vnitr. Lek."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Weerd, J.C.V., Wegberg, A.M.J.V., Boer, T.S., Engelke, U.F.H., Coene, K.L.M., Wevers, R.A., Bakker, S.J.L., Blaauw, P., Groen, J., and Spronsen, F.J.V. (2024). Impact of phenylketonuria on the serum metabolome and plasma lipidome: A study in early-treated patients. Metabolites, 14.","DOI":"10.3390\/metabo14090479"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6895","DOI":"10.1038\/s41467-024-51174-3","article-title":"SLC17A1\/3 transporters mediate renal excretion of Lac-Phe in mice and humans","volume":"15","author":"Li","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101558","DOI":"10.1016\/j.jcmgh.2025.101558","article-title":"Exercise-induced metabolite N-lactoyl-phenylalanine ameliorates colitis by inhibiting M1 macrophage polarization via the suppression of the NF-\u03baB signaling pathway","volume":"19","author":"Yu","year":"2025","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yang, K., Xu, J., Fan, M., Tu, F., Wang, X., Ha, T., Williams, D.L., and Li, C. (2020). Lactate suppresses macrophage pro-inflammatory response to LPS stimulation by inhibition of YAP and NF-\u03baB activation via GPR81-mediated signaling. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.587913"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/joim.20090","article-title":"Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes","volume":"297","author":"Henderson","year":"2025","journal-title":"J. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1161\/ATVBAHA.122.318871","article-title":"Precise metabolomics defines systemic metabolic dysregulation distinct to acute myocardial infarction associated with diabetes","volume":"43","author":"Xia","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s11306-025-02260-0","article-title":"Exercise intensity determines circulating levels of Lac-Phe and other exerkines: A randomized crossover trial","volume":"21","author":"Weber","year":"2025","journal-title":"Metabolomics"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bauhaus, H., M\u00f6ller, T., Keller, S., Thomas, A., Braun, H., Wahl, P., and Thevis, M. (2025). Proof-of-concept of a prior validated LC-MS\/MS method for detection of N-lactoyl-phenylalanine in dried blood spots before, during and after a performance diagnostic test of junior squad triathletes. Front. Sports Act. Living, 7.","DOI":"10.3389\/fspor.2025.1600714"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41392-024-02082-x","article-title":"Lactate and lactylation in cancer","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41420-025-02609-3","article-title":"Exercise-induced lactate suppresses ccRCC via CNDP2-mediated depletion of intracellular amino acids","volume":"11","author":"Miao","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Novelli, G., Calcaterra, G., Casciani, F., Pecorelli, S., and Mehta, J.L. (2024). \u2018Exerkines\u2019: A comprehensive term for the factors produced in response to exercise. Biomedicines, 12.","DOI":"10.3390\/biomedicines12091975"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mielniczek, M., and Aune, T.K. (2024). The effect of high-intensity interval training (HIIT) on brain-derived neurotrophic factor levels (BNDF): A systematic review. Brain Sci., 15.","DOI":"10.3390\/brainsci15010034"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"C1437","DOI":"10.1152\/ajpcell.00427.2023","article-title":"Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model","volume":"326","author":"Skarp","year":"2024","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.18632\/aging.206325","article-title":"L-\u03b2-aminoisobutyric acid (L-BAIBA) in combination with voluntary wheel running exercise enhances musculoskeletal properties in middle-age male mice","volume":"17","author":"Vallejo","year":"2025","journal-title":"Aging"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhu, X., Chen, W., Pinho, R.A., and Thirupathi, A. (2025). Lactate-induced metabolic signaling is the potential mechanism for reshaping the brain function\u2014Role of physical exercise. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1598419"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e18413","DOI":"10.7717\/peerj.18413","article-title":"The role and underlying mechanisms of irisin in exercise-mediated cardiovascular protection","volume":"12","author":"Guo","year":"2024","journal-title":"PeerJ"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101679","DOI":"10.1016\/j.jbc.2022.101679","article-title":"FNDC5\/irisin facilitates muscle-adipose-bone connectivity through ubiquitination-dependent activation of runt-related transcriptional factors RUNX1\/2","volume":"298","author":"He","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Thrones, M., Rawliuk, T., Cordingley, D.M., and Cornish, S.M. (2026). The myokine FGF-21 responds in a time-dependent manner to three different types of acute exercise. Muscles, 5.","DOI":"10.3390\/muscles5010003"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E1105","DOI":"10.1152\/ajpendo.00348.2009","article-title":"Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models\u2014Association with liver and adipose tissue effects","volume":"297","author":"Xu","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.bbrc.2016.03.159","article-title":"Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle","volume":"473","author":"Ikeda","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7591","DOI":"10.1074\/jbc.M207232200","article-title":"Calmodulin mediates brain-derived neurotrophic factor cell survival signaling upstream of Akt kinase in embryonic neocortical neurons","volume":"278","author":"Cheng","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Cheng, Y., Liu, Y., Ma, J., Li, Z., Han, E., and Bo, S. (2025). Effects of three aerobic exercise modalities (walking, running, and cycling) on circulating brain-derived neurotrophic factor in older adults: A systematic review and meta-analysis. Front. Aging Neurosci., 17.","DOI":"10.3389\/fnagi.2025.1673786"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101077","DOI":"10.1016\/j.jshs.2025.101077","article-title":"Exercise suppresses osteoclastogenesis by increasing the secretion of muscle-derived L-\u03b2-aminoisobutyric acid","volume":"16","author":"Huang","year":"2025","journal-title":"J. Sport Health Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.celrep.2018.01.041","article-title":"\u03b2-aminoisobutyric acid, l-BAIBA, is a muscle-derived osteocyte survival factor","volume":"22","author":"Kitase","year":"2018","journal-title":"Cell Rep."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/441\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T08:12:22Z","timestamp":1775117542000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/441"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["antiox15040441"],"URL":"https:\/\/doi.org\/10.3390\/antiox15040441","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]}}}