{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:44:46Z","timestamp":1785415486728,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32560225"],"award-info":[{"award-number":["32560225"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32560225"],"award-info":[{"award-number":["32560225"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Jiangxi Province Major Discipline Academic and Technical Leaders Training Project","award":["20243BCE51140"],"award-info":[{"award-number":["20243BCE51140"]}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20242BAB20270"],"award-info":[{"award-number":["20242BAB20270"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Research and Development Project of Yichun City, Jiangxi Province","award":["2024ZDYFJH01"],"award-info":[{"award-number":["2024ZDYFJH01"]}]},{"name":"Graduate Innovation Special Fund Project of Jiangxi Province","award":["YC2025-S807"],"award-info":[{"award-number":["YC2025-S807"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tyrosinase is a pivotal therapeutic target for hyperpigmentation disorders, yet current inhibitors frequently exhibit limited potency and suboptimal safety. Here, we employed structure-based virtual screening of an FDA-approved drug library against a refined human tyrosinase homology model, identifying methotrexate and selinexor as potent anti-melanogenic candidates. Both compounds markedly suppressed cellular tyrosinase activity and melanin synthesis (IC50 &lt; 1 \u00b5M) in MNT-1 melanoma cells. Mechanistically, they orchestrate a multi-pronged downregulation of microphthalmia-associated transcription factor (MITF) by attenuating cAMP\/PKA\/CREB signaling, promoting \u03b2-catenin degradation, and accelerating MITF proteolysis via AKT\/ERK activation. Additionally, they bolster the intracellular antioxidant defense system. These findings unveil a sophisticated regulatory network and suggest that with strict control of systemic exposure through optimized topical formulations, these FDA-approved agents could be further investigated as potential localized treatments for pigmentary disorders.<\/jats:p>","DOI":"10.3390\/cells15121070","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:08Z","timestamp":1781229128000},"page":"1070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure-Based Virtual Screening and Mechanistic Characterization of Methotrexate and Selinexor as Potent Anti-Melanogenic Agents via Multi-Pathway Suppression of MITF"],"prefix":"10.3390","volume":"15","author":[{"given":"Zhongwei","family":"Zhang","sequence":"first","affiliation":[{"name":"Jiangxi Key Laboratory of Natural Microbial Medicine Research, School of Pharmacy, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiran","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangxi Key Laboratory of Natural Microbial Medicine Research, School of Pharmacy, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonglan","family":"Shi","sequence":"additional","affiliation":[{"name":"Jiangxi Key Laboratory of Natural Microbial Medicine Research, School of Pharmacy, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Bai","sequence":"additional","affiliation":[{"name":"Jiangxi Key Laboratory of Natural Microbial Medicine Research, School of Pharmacy, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peipei","family":"Yin","sequence":"additional","affiliation":[{"name":"Jiangxi Key Laboratory of Natural Microbial Medicine Research, School of Pharmacy, Yichun University, Yichun 336000, China"},{"name":"Jiangxi Provincial Engineering Research Center for Recycling Technology of Traditional Chinese Medicine Herbal Residue, School of Pharmacy, Yichun University, Yichun 336000, China"},{"name":"Yichun City Natural Medicines Bionic Delivery Technology Innovation Center, School of Pharmacy, Yichun University, Yichun 336000, China"},{"name":"Yichun University Center for Innovative Technologies in Gene-Based Precision Therapeutics, School of Pharmacy, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0584-0178","authenticated-orcid":false,"given":"Lingguang","family":"Yang","sequence":"additional","affiliation":[{"name":"Jiangxi Key Laboratory of Natural Microbial Medicine Research, School of Pharmacy, Yichun University, Yichun 336000, China"},{"name":"Jiangxi Provincial Engineering Research Center for Recycling Technology of Traditional Chinese Medicine Herbal Residue, School of Pharmacy, Yichun University, Yichun 336000, China"},{"name":"Yichun City Natural Medicines Bionic Delivery Technology Innovation Center, School of Pharmacy, Yichun University, Yichun 336000, China"},{"name":"Yichun University Center for Innovative Technologies in Gene-Based Precision Therapeutics, School of Pharmacy, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, K., Lin, S., Zhou, P., Guo, Y., Lin, S., and Ji, C. 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