{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T17:49:32Z","timestamp":1776361772952,"version":"3.51.2"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science and Innovation\/Agencia Estatal de Investigaci\u00f3n","award":["MCIN\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MCIN\/AEI\/10.13039\/501100011033"]}]},{"name":"Spanish Ministry of Science and Innovation\/Agencia Estatal de Investigaci\u00f3n","award":["PID2020-114632GB-100"],"award-info":[{"award-number":["PID2020-114632GB-100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pheomelanin is a sulfur-containing pigment produced by melanocytes notably in individuals with red hair\/fair skin and animals with orange integumentary structures. Pheomelanin is not photoprotective as the dark eumelanin, but is cytotoxic, being related to a high risk of melanoma independently of UV radiation. This questions any physiological role for the pigment. The persistence of genetic variants promoting pheomelanogenesis may be explained by a contribution to cysteine homeostasis, as the toxicity of excessive cysteine accumulation in melanocytes may be avoided when the amino acid is used to build the inert pigment. Such function remains untested. Recently, melanocortin-1 receptor (MC1R) signaling, which hinders pheomelanogenesis, has been shown to be highly dependent on its degree of palmitoylation. Finding an efficient selective inhibitor of the enzyme that catalyzes depalmitoylation (APT2), ML349, has thus opened a convenient pharmacological method to block pheomelanogenesis and thus test for its physiological role. Here, a simultaneous treatment with dietary cysteine and ML349 impaired feather pheomelanin-based pigmentation in male zebra finches Taeniopygia guttata. ML349 treatment resulted in the increase in systemic oxidative damage (malondialdehyde) when accounting for the antioxidant capacity of orange, pheomelanin-producing follicular melanocytes by means of NFE2L2 expression, but not that of black, eumelanin-producing melanocytes. Females, that do not produce pheomelanin, were not affected by ML349, but cysteine supplementation tended to increase their oxidative damage. These findings prove a role of pheomelanin in cysteine homeostasis, opening a better understanding of melanoma risk through environmental factors affecting cysteine availability, and the evolutionary predictors of animal color diversity.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgaf391","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T13:02:12Z","timestamp":1767704532000},"source":"Crossref","is-referenced-by-count":1,"title":["MC1R depalmitoylation inhibition reveals a physiological role for pheomelanin"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6523-8592","authenticated-orcid":false,"given":"Ismael","family":"Galv\u00e1n","sequence":"first","affiliation":[{"name":"Department of Evolutionary Ecology, National Museum of Natural Sciences, CSIC , C\/Jos\u00e9 Guti\u00e9rrez Abascal 2, Madrid 28006 ,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6519-5245","authenticated-orcid":false,"given":"Marina","family":"Garc\u00eda-Guerra","sequence":"additional","affiliation":[{"name":"Department of Evolutionary Ecology, National Museum of Natural Sciences, CSIC , C\/Jos\u00e9 Guti\u00e9rrez Abascal 2, Madrid 28006 ,","place":["Spain"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8876-6670","authenticated-orcid":false,"given":"Marta","family":"Araujo-Roque","sequence":"additional","affiliation":[{"name":"Department of Evolutionary Ecology, National Museum of Natural Sciences, CSIC , C\/Jos\u00e9 Guti\u00e9rrez Abascal 2, Madrid 28006 ,","place":["Spain"]}]}],"member":"286","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"2026010608020801700_pgaf391-B1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/pcmr.12257","article-title":"MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation","volume":"27","author":"Garc\u00eda-Borr\u00f3n","year":"2014","journal-title":"Pigment Cell Melanoma Res"},{"key":"2026010608020801700_pgaf391-B2","doi-asserted-by":"crossref","first-page":"13845","DOI":"10.1073\/pnas.1201917110","article-title":"MC1R and cAMP signaling inhibit cdc25B activity and delay cell cycle progression in melanoma cells","volume":"110","author":"Lyons","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026010608020801700_pgaf391-B3","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.jid.2021.06.018","article-title":"MC1R functions, expression, and implications for targeted therapy","volume":"142","author":"Guida","year":"2022","journal-title":"J Invest Dermatol"},{"key":"2026010608020801700_pgaf391-B4","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0304-4165(97)00068-8","article-title":"Chemical characterization of pheomelanogenesis starting from dihydroxyphenylalanine or tyrosine and cysteine: effects of tyrosinase and cysteine concentrations and reaction time","volume":"1336","author":"Ozeki","year":"1997","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"2026010608020801700_pgaf391-B5","doi-asserted-by":"crossref","first-page":"15076","DOI":"10.1073\/pnas.0403994101","article-title":"Melanin acts as a potent UVB photosensitizer to cause an atypical mode of cell death in murine skin","volume":"101","author":"Takeuchi","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026010608020801700_pgaf391-B6","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1126\/science.1256022","article-title":"Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure","volume":"347","author":"Premi","year":"2015","journal-title":"Science"},{"key":"2026010608020801700_pgaf391-B7","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/nature11624","article-title":"An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair\/fair skin background","volume":"491","author":"Mitra","year":"2012","journal-title":"Nature"},{"key":"2026010608020801700_pgaf391-B8","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/bies.201300020","article-title":"How does pheomelanin synthesis contribute to melanomagenesis?","volume":"35","author":"Morgan","year":"2013","journal-title":"BioEssays"},{"key":"2026010608020801700_pgaf391-B9","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/pcmr.12262","article-title":"Pheomelanin-induced oxidative stress: bright and dark chemistry bridging red hair phenotype and melanoma","volume":"27","author":"Napolitano","year":"2014","journal-title":"Pigment Cell Melanoma Res"},{"key":"2026010608020801700_pgaf391-B10","doi-asserted-by":"crossref","first-page":"101582","DOI":"10.1016\/j.canep.2019.101582","article-title":"High SLC7A11 expression in normal skin of melanoma 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