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Intracellular serine availability is shaped by nutrient conditions, glycolytic flux, and activity of the serine synthesis pathway, and these fluctuations are sensed to elicit coordinated metabolic and signaling responses. This review discusses mechanisms by which serine modulates cell growth and stress responses, with particular emphasis on its interaction with central nutrient-sensing pathways, including mTORC1 and the integrated stress response. In parallel, serine-driven one-carbon metabolism is examined for its role in supporting nucleotide biosynthesis, methylation reactions, and redox homeostasis through folate-dependent pathways and NADPH generation, thereby coupling anabolic processes to the maintenance of redox balance and genome integrity. In addition to intracellular functions, serine contributes to intercellular signaling. Conversion of l-serine to d-serine mediates neuromodulatory activity via N-methyl-d-aspartate receptors, while serine availability also influences immune cell function, inflammatory signaling, and host\u2013microbe interactions. Dysregulation of serine metabolism and signaling is further considered in the context of disease states, including cancer, neurodegeneration, and metabolic disorders. Together, these observations support a framework in which serine functions as an information-bearing metabolic signal that coordinates the biosynthetic capacity with cellular adaptation and intercellular communication.<\/jats:p>","DOI":"10.1021\/acs.biochem.6c00353","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T19:02:09Z","timestamp":1786474929000},"page":"2629-2643","source":"Crossref","is-referenced-by-count":0,"title":["Serine: From\nMetabolic Intermediate to Signaling Entity"],"prefix":"10.1021","volume":"65","author":[{"given":"Sharon","family":"Spizzichino","sequence":"first","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Maria","family":"Varchetta","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia Elizabeth","family":"Borsatti","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Chillemi","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Arese","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Paone","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0682-023X","authenticated-orcid":true,"given":"Serena","family":"Rinaldo","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4621-2135","authenticated-orcid":true,"given":"Francesca","family":"Cutruzzola\u0300","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome , , P. le A. Moro 5 , ,","place":["Rome, Italy, 00185"]},{"name":"Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti , ,","place":["Rome, Italy, 00161"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2026090306414170700_cit1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0083-6729(08)00401-9","article-title":"Folate-mediated one-carbon metabolism","volume":"79","author":"Fox","year":"2008","journal-title":"Vitam. Horm."},{"key":"2026090306414170700_cit2","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nrm.2017.107","article-title":"Sphingolipids and their metabolism\nin physiology and\ndisease","volume":"19","author":"Hannun","year":"2018","journal-title":"Nat. Rev. Mol. 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Rev. Nutr."},{"key":"2026090306414170700_cit10","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nature13236","article-title":"Quantitative\nflux analysis reveals folate-dependent NADPH production","volume":"510","author":"Fan","year":"2014","journal-title":"Nature"},{"key":"2026090306414170700_cit11","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/nchembio.2070","article-title":"A PHGDH inhibitor\nreveals coordination of serine synthesis and one-carbon unit fate","volume":"12","author":"Pacold","year":"2016","journal-title":"Nat. Chem. 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