{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T13:11:40Z","timestamp":1773493900937,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chemistry &amp;amp; Biodiversity"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Melanin protects skin from ultraviolet rays, but excessive or misdistributed synthesis can cause issues like melasma, freckles, or melanoma. Rhein from traditional Chinese herbs shows various bioactivities, with recent structural modifications enhancing its derivatives, but its effect on melanogenesis is unreported. The study reports synthesizing and evaluating\n                    <jats:bold>D16<\/jats:bold>\n                    , Rhein\u2010based proteolysis targeting chimera (PROTACs) utilizing pomalidomide as an E3 ligand.\n                    <jats:bold>D16<\/jats:bold>\n                    exhibited significantly reduced cytotoxicity, with half\u2010maximal inhibitory concentration values exceeding 100 \u00b5M in both B16\u2010F10 melanoma and human immortalized keratinocyte cells, indicating a low level of toxicity. In addition, mechanistic studies revealed that\n                    <jats:bold>D16<\/jats:bold>\n                    suppresses melanin production primarily through the melanocortin 1 receptor\/\u03b1\u2010melanocyte\u2010stimulating hormone signaling pathway, with further analysis suggesting phosphorylated cyclic adenosine monophosphate\u2010response element binding protein (pCREB) as a key target. Through pCREB degradation,\n                    <jats:bold>D16<\/jats:bold>\n                    disrupts microphthalmia\u2010associated transcription factor transcription, leading to reduced levels of tyrosine. Molecular docking studies further confirmed strong binding between\n                    <jats:bold>D16<\/jats:bold>\n                    and pCREB. Animal experiment results indicated that\n                    <jats:bold>D16<\/jats:bold>\n                    effectively suppressed melanogenesis in mice. These findings underscore the potential of\n                    <jats:bold>D16<\/jats:bold>\n                    to treat melanin\u2010related disorders by targeting pCREB, advancing both the therapeutic utility of PROTACs and the application of pCREB modulation in pigmentation treatments.\n                  <\/jats:p>","DOI":"10.1002\/cbdv.202501651","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T19:38:38Z","timestamp":1754681918000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Disrupting the MC1R\/\u03b1\u2010MSH\u2010pCREB\u2010MITF Axis: Rhein\u2010based PROTAC D16 as a Potent Melanogenesis Inhibitor"],"prefix":"10.1002","volume":"22","author":[{"given":"Meng","family":"Xu","sequence":"first","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peixi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyi","family":"He","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huagong","family":"Zeng","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanxi","family":"Xia","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiming","family":"Lu","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi","family":"Huang","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shien","family":"Luo","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueping","family":"Huang","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muge","family":"Chen","sequence":"additional","affiliation":[{"name":"Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities Key Laboratory of Xiamen Marine and Gene Drugs School of Medicine Huaqiao University  Quanzhou P. R. 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