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Here we systematically delineate how TF3 targets Pin1 to suppress HCC through an integrated approach combining computational simulations, enzyme assay and cell-based assays. TF3 spontaneously occupies the active site of Pin1 with a docking score of \u22128.9 kcal\/mol, inhibiting its PPIase activity (IC50 = 60.33 \u03bcmol\/L) and yielding a binding constant (Ka) of 3.1 \u00d7 105 mol\/L. Drug affinity responsive target stability (DARTS) assays further corroborated that TF3 directly engages Pin1 within HCC cells. Functionally, TF3 potently suppressed the viability of HepG2, SK-Hep-1 and Huh-7 cells in both dose- and time-dependent manners (IC50 = 61.22, 14.09 and 69.85 \u03bcmol\/L at 24 h, respectively), and exhibited a modest selectivity window against the viability of L02 and THLE-2 cells (IC50 = 133.43 and 90.29 \u03bcmol\/L at 24 h, respectively). In addition, TF3 triggers mitochondrial-mediated apoptosis, evidenced by ROS accumulation, loss of mitochondrial membrane potential, an elevated Bax\/Bcl-2 ratio, cytochrome c release and enhanced PARP cleavage, and induces G2\/M phase arrest. It also robustly inhibits HCC cell proliferation, invasion and migration, coinciding with downregulation of proteins governing cell cycle progression and invasive behavior. Transcriptome profiling coupled with enrichment analysis discovered that TF3 treatment differentially regulated 5009 genes, which were prominently enriched in pathways linked to apoptosis, cell cycle control, MAPK and PI3K\/AKT signaling pathways. Western blotting analysis revealed that TF3 selectively suppresses phosphorylation of p38 and the PI3K\/AKT cascade, activating JNK phosphorylation. In summary, our findings indicate that TF3 suppresses HCC proliferation by targeting Pin1, with attendant modulation of the MAPK and PI3K\/AKT pathways, thereby presenting a potential candidate for targeted HCC therapy.<\/jats:p>","DOI":"10.3390\/biom16040583","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T14:24:58Z","timestamp":1776176698000},"page":"583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Theaflavin-3,3\u2032-Digallate Targets Pin1 to Suppress Hepatocellular Carcinoma Malignant Proliferation Through Modulation of MAPK and PI3K\/AKT Signaling Pathways In Vitro"],"prefix":"10.3390","volume":"16","author":[{"given":"Shaoli","family":"Lv","sequence":"first","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Tao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqing","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinling","family":"Liao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayang","family":"Xie","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyuan","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity, Health Commission of Jiangxi Province, School of Basic Medicine, Nanchang Medical College, Nanchang 330052, China"},{"name":"Jiangxi Provincial Education Department Key Laboratory for the Application of Key Technologies in Drug Screening for Inflammatory Diseases and Phlegm Syndrome, Nanchang 330052, China"},{"name":"The Jiangxi Province Key Laboratory of Hematologic Diseases, Nanchang 330052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/s41571-023-00825-3","article-title":"Global trends in hepatocellular carcinoma epidemiology: Implications for screening, prevention and therapy","volume":"20","author":"Singal","year":"2023","journal-title":"Nat. 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