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Triptophenolide (TRI), a diterpenoid compound, has shown anti-proliferative activity in breast and pancreatic cancers, but its role in liver cancer remains largely unexplored. In this study, TRI significantly inhibited the proliferation of HepG2 (hepatoblastoma) and HuH7 (hepatocellular carcinoma) cells in a dose-dependent manner, with IC50 values decreasing from 279.9 to 229.4 \u00b5g\/mL (24\u201348 h) in HepG2 and from 441.1 to 282.6 \u00b5g\/mL in HuH7. Colony formation assays confirmed the suppression of HCC cell growth. TRI also promoted apoptosis, increasing apoptotic rates to 68.99% in HepG2 and 43.34% in HuH7 at 400 \u00b5g\/mL (48 h). Cell cycle analysis revealed S-phase arrest, with TRI raising the S-phase population to 42.02% and 45.38%, respectively. Mechanistically, TRI upregulated pro-apoptotic genes (TP53, CASP3\/9\/10, BAX, BAK1, BID, BIM) and proteins, activating the mitochondrial apoptotic pathway. In vivo, TRI (10 mg\/kg) markedly reduced tumor volumes in HepG2 and HuH7 xenografts compared with controls, without obvious systemic toxicity. These findings suggest that TRI exerts anti-proliferative, pro-apoptotic, and cell cycle regulatory effects in HCC. However, further preclinical studies are warranted to elucidate its mechanisms and evaluate its safety profile.<\/jats:p>","DOI":"10.3390\/ijms27073251","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T02:06:21Z","timestamp":1775441181000},"page":"3251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Preclinical Evaluation of Triptophenolide-Induced Apoptosis in Hepatoblastoma (HepG2) and Hepatocellular Carcinoma (HuH7) Cell Lines"],"prefix":"10.3390","volume":"27","author":[{"given":"Zufa","family":"Sabeel","sequence":"first","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolan","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyang","family":"Pan","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Ying","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2856-7167","authenticated-orcid":false,"given":"Zhao","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, Beijing University of Chemical Technology, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"ref_1","first-page":"20","article-title":"Burden of liver cancer in adolescents and young adults aged 15\u201349 years in China: A comprehensive analysis based on the Global Burden of Disease study (1990\u20132021)","volume":"11","author":"Zou","year":"2025","journal-title":"Hepatoma Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Voskamp, S., Nelson, J., and Speck, K.E. 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