{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:34:12Z","timestamp":1792805652600,"version":"4.5.0"},"reference-count":64,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovation Fund of Chulalongkorn University","award":["HEA-FF-68-375-3300-022"],"award-info":[{"award-number":["HEA-FF-68-375-3300-022"]}],"id":[{"id":"https:\/\/ror.org\/028wp3y58","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Excessive melanin production causes hyperpigmentation disorders such as freckles, melasma, and age spots, affecting appearance and quality of life. Tyrosinase is the key enzyme controlling melanin synthesis, and natural compounds are being explored as effective tyrosinase inhibitors. Fisetin, a dietary flavonoid found in fruits and vegetables like grapes and onions, is known for its anti-inflammatory and anticancer properties, but its anti-melanogenic activity remains unclear. This study demonstrated that fisetin, up to 60 \u03bcM, is non-toxic and significantly decreases tyrosinase activity and melanin content in human melanoma cells. Mechanistically, fisetin activates PKC\u03b1, leading to phosphorylation and degradation of \u03b2-catenin, thereby downregulating MITF expression. Additionally, it activates ERK and AKT\/GSK3\u03b2 pathways, promoting ubiquitination and proteasomal degradation of MITF, resulting in reduced levels of tyrosinase, TRP-1, and TRP-2. The proteasome inhibitor MG132 confirmed that fisetin accelerates \u03b2-catenin and MITF degradation. Additionally, inhibition of the PI3K\/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin\u2019s reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKC\u03b1, \u03b2-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation.<\/jats:p>","DOI":"10.3390\/ijms262311739","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T13:53:30Z","timestamp":1764856410000},"page":"11739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanistic Insights into Anti-Melanogenic Effects of Fisetin: PKC\u03b1-Induced \u03b2-Catenin Degradation, ERK\/MITF Inhibition, and Direct Tyrosinase Suppression"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7906-0986","authenticated-orcid":false,"given":"Zin Zin","family":"Ei","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satapat","family":"Racha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Interdisciplinary Program in Pharmacology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbin","family":"Zou","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pithi","family":"Chanvorachote","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand"},{"name":"Sustainable Environment Research Institute, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bento-Lopes, L., Caba\u00e7o, L.C., Charneca, J., Neto, M.V., Seabra, M.C., and Barral, D.C. 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