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In this study, we aimed to identify a mild active substance in Morus alba L. that can inhibit the pulmonary metastasis of HCC and reduce the drug resistance of clinical therapies. Further deepen the understanding of the anti-cancer functions of the mulberry active substances. In this study, we have screened and identified a flavonoid compound extracted from the root bark of the Morus alba L. named Kuwanon A (KA). Our research demonstrated that KA directly targeted the YWHAB (tyrosine 3-monooxygenase\/tryptophan 5-monooxygenase activation protein beta) and mediated its dimer dissociation. Thereby inhibiting the MAPK pathway and affecting downstream biological functions, including cell cycle arrest and migration\/invasion inhibition. The experiment results proved that KA could inhibit the proliferation and metastasis of highly metastatic HCC cells both in vitro and in vivo. Additionally, when KA was combined with the clinical drug sorafenib, it exhibited a synergistic effect in inhibiting HCC cell proliferation, migration, and invasion. In conclusion, KA demonstrated a favorable anti-tumor effect in HCC cells.<\/jats:p>","DOI":"10.3390\/cells14191487","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T15:54:54Z","timestamp":1758642894000},"page":"1487","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Kuwanon A Targeted YWHAB in Hepatocellular Carcinoma Cells to Inhibit the Raf\/MEK\/ERK Signaling Pathway"],"prefix":"10.3390","volume":"14","author":[{"given":"Jingyang","family":"Xu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Chang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"},{"name":"Jinfeng Laboratory, Chongqing 401329, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhao","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Zhong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Targeting Oncology, Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1178-1570","authenticated-orcid":false,"given":"Hongjuan","family":"Cui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China"},{"name":"Jinfeng Laboratory, Chongqing 401329, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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