{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:18:17Z","timestamp":1785403097869,"version":"3.56.0"},"reference-count":58,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFA0911700"],"award-info":[{"award-number":["2021YFA0911700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31600016"],"award-info":[{"award-number":["31600016"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["31600016"],"award-info":[{"award-number":["31600016"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ningbo Major Research and Development Plan Project","award":["2024Z228"],"award-info":[{"award-number":["2024Z228"]}]},{"name":"Zhejiang Provincial Medical and Health Science and Technology Project","award":["2025KY1338"],"award-info":[{"award-number":["2025KY1338"]}]},{"name":"Zhejiang Provincial Medical and Health Science and Technology Project","award":["2025HY0967"],"award-info":[{"award-number":["2025HY0967"]}]},{"name":"Ningbo Public Welfare Science and Technology Foundation","award":["2024S175"],"award-info":[{"award-number":["2024S175"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Melanoma remains highly lethal with frequent resistance to current therapies. Here we identify a marine-derived cyclopentapeptide, turnagainolide B, as a potent anti-melanoma agent that selectively kills B16-F10 melanoma cells (IC50 = 50 \u03bcM) with low toxicity to normal skin cells. Using bioassay-guided isolation, we also obtained a new analogue, turnagainolide H, and elucidated their structures and biosynthetic pathways. Mechanistically, turnagainolide B induces a previously undescribed \u201cdual-hit\u201d autophagic signature: it simultaneously promotes autophagy initiation (via PI3K\/mTOR suppression, evidenced by ATG5 and LC3B-II upregulation) and blocks autophagic degradation (evidenced by p62 accumulation). Co-treatment with chloroquine partially rescued cell viability and decreased LC3B levels, confirming that cell death depends on active autophagic flux disruption. Transcriptomic analysis, together with AI target prediction and docking, identified PI3K as a potential direct target, with downregulation of PI3K, mTOR, and BNIP3 supporting an imbalanced autophagic state. In a syngeneic mouse melanoma model, turnagainolide B significantly suppressed tumor growth, reduced melanin content and Ki67 expression, and enhanced CD8+ T cell infiltration. Collectively, this work expands the chemical diversity of the turnagainolide family, uncovers a unique \u201cdual-hit\u201d autophagic mechanism, and establishes turnagainolide B as a promising lead for melanoma therapy.<\/jats:p>","DOI":"10.3390\/md24070235","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T11:39:11Z","timestamp":1783078751000},"page":"235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Marine-Derived Cyclopentapeptide Turnagainolide B Suppresses Melanoma via Autophagic Flux Disruption and Inhibits Tumorigenesis In Vivo"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-5825","authenticated-orcid":false,"given":"Guoyue","family":"Wan","sequence":"first","affiliation":[{"name":"Center of Reproduction, Development & Aging, Cancer Center and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China"},{"name":"State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6497-4117","authenticated-orcid":false,"given":"Keyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[{"name":"College of New Materials and Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren-He","family":"Xu","sequence":"additional","affiliation":[{"name":"Center of Reproduction, Development & Aging, Cancer Center and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Jin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0578-1091","authenticated-orcid":false,"given":"Liwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Health Science Center, Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/CM9.0000000000003416","article-title":"Recent global patterns in skin cancer incidence, mortality, and prevalence","volume":"138","author":"Wang","year":"2025","journal-title":"Chin. 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