{"title":"RTA‑408 induces p38‑dependent apoptosis and suppresses cell viability in hepatocellular carcinoma cells.","authors":"Wei-Chieh Chen, Yoon Bin Chong, Hung-Pei Tsai, Tzu-Ting Tseng, Chen-Yu Wang, Shih-Hsun Kuo, Sheau-Fang Yang, Chun-Chieh Wu","doi":"10.1080/20450923.2026.2659967","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Hepatocellular carcinoma (HCC) remains difficult to treat, highlighting the need for new therapeutic strategies. RTA-408 (omaveloxolone), a synthetic oleanane triterpenoid and NRF2 pathway modulator, has reported anticancer activity, but its mechanisms in HCC are not fully understood.</p><p><strong>Materials and methods: </strong>HepG2 and PLC/PRF/5 (PP5) cells were treated with RTA-408 for 24 h. Cell viability, apoptosis, and signaling pathways were evaluated using MTT assay, Annexin V/7-AAD flow cytometry, and western blotting. The role of p38 signaling was examined using the p38 inhibitor SB203580.</p><p><strong>Results: </strong>RTA-408 reduced cell viability in a concentration-dependent manner and increased apoptosis in both cell lines. At 600 nM, apoptosis increased to approximately 18.43% in HepG2 cells and 24.71% in PP5 cells. RTA-408 increased p38 phosphorylation and NRF2 expression and was accompanied by LC3B and p62 accumulation and elevated cleaved caspase-3. Inhibition of p38 partially restored cell viability and reduced apoptosis.</p><p><strong>Conclusion: </strong>RTA-408 suppresses HCC cell survival through a p38-dependent stress response associated with NRF2 activation and LC3B/p62 accumulation.</p>","PeriodicalId":44854,"journal":{"name":"Hepatic Oncology","volume":"13 1","pages":"2659967"},"PeriodicalIF":1.3000,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123068/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hepatic Oncology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1080/20450923.2026.2659967","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/4/27 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: Hepatocellular carcinoma (HCC) remains difficult to treat, highlighting the need for new therapeutic strategies. RTA-408 (omaveloxolone), a synthetic oleanane triterpenoid and NRF2 pathway modulator, has reported anticancer activity, but its mechanisms in HCC are not fully understood.
Materials and methods: HepG2 and PLC/PRF/5 (PP5) cells were treated with RTA-408 for 24 h. Cell viability, apoptosis, and signaling pathways were evaluated using MTT assay, Annexin V/7-AAD flow cytometry, and western blotting. The role of p38 signaling was examined using the p38 inhibitor SB203580.
Results: RTA-408 reduced cell viability in a concentration-dependent manner and increased apoptosis in both cell lines. At 600 nM, apoptosis increased to approximately 18.43% in HepG2 cells and 24.71% in PP5 cells. RTA-408 increased p38 phosphorylation and NRF2 expression and was accompanied by LC3B and p62 accumulation and elevated cleaved caspase-3. Inhibition of p38 partially restored cell viability and reduced apoptosis.
Conclusion: RTA-408 suppresses HCC cell survival through a p38-dependent stress response associated with NRF2 activation and LC3B/p62 accumulation.
期刊介绍：
Primary liver cancer is the sixth most common cancer in the world, and the third most common cause of death from malignant disease. Traditionally more common in developing countries, hepatocellular carcinoma is becoming increasingly prevalent in the Western world, primarily due to an increase in hepatitis C virus infection. Emerging risk factors, such as non-alcoholic fatty liver disease and obesity are also of concern for the future. In addition, metastatic tumors of the liver are more common than primary disease. Some studies report hepatic metastases in as many as 40 to 50% of adult patients with extrahepatic primary tumors. Hepatic Oncology publishes original research studies and reviews addressing preventive, diagnostic and therapeutic approaches to all types of cancer of the liver, in both the adult and pediatric populations. The journal also highlights significant advances in basic and translational research, and places them in context for future therapy. Hepatic Oncology provides a forum to report and debate all aspects of cancer of the liver and bile ducts. The journal publishes original research studies, full reviews and commentaries, with all articles subject to independent review by a minimum of three independent experts. Unsolicited article proposals are welcomed and authors are required to comply fully with the journal''s Disclosure & Conflict of Interest Policy as well as major publishing guidelines, including ICMJE and GPP3.
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