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Understanding the role of TAMs in HCC is crucial for developing novel therapeutic strategies. Macrophages exhibit plasticity, resulting in M1 and M2 phenotypes, with M1 macrophages displaying antitumor properties and M2 macrophages promoting tumor progression. Targeting TAMs to alter their polarization could offer new avenues for HCC treatment. \u03b2,\u03b2-dimethylacrylalkannin (DMAKN), a natural naphthoquinone, has gained attention for its antitumor properties. However, its impact on TAMs modulation remains unclear. This study investigates DMAKN\u2019s modulation of TAMs and its anti-HCC activity. Using an in vitro model with THP-1 cells, we induced M1 macrophages with LPS\/IFN-\u03b3 and M2 macrophages with IL-4\/IL-13, confirming polarization with specific markers. Co-culturing these macrophages with HCC cells showed that M1 cells inhibited HCC growth, while M2 cells promoted it. Screening for non-toxic DMAKN concentrations revealed its ability to induce M1 polarization and enhance LPS\/IFN-\u03b3-induced M1 macrophages, both showing anti-HCC effects. Conversely, DMAKN suppressed IL-4\/IL-13-induced M2 polarization, inhibiting M2 macrophages\u2019 promotion of HCC cell viability. In summary, DMAKN induces and enhances M1 polarization while inhibiting M2 polarization of macrophages, thereby inhibiting HCC cell growth. These findings suggest that DMAKN has the potential to regulate TAMs in HCC, offering promise for future therapeutic development.<\/jats:p>","DOI":"10.3390\/molecules29163919","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T01:38:45Z","timestamp":1724117925000},"page":"3919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["\u03b2,\u03b2-Dimethylacrylalkannin, a Natural Naphthoquinone, Inhibits the Growth of Hepatocellular Carcinoma Cells by Modulating Tumor-Associated Macrophages"],"prefix":"10.3390","volume":"29","author":[{"given":"Li-Sha","family":"Shen","sequence":"first","affiliation":[{"name":"Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China"},{"name":"Sichuan\u2013Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing 400065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zesi","family":"Lin","sequence":"additional","affiliation":[{"name":"Southern Medical University of Hospital of Integrated Traditional Chinese Medicine and Western Medicine, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Hong","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Shan","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Fang","family":"Qiao","sequence":"additional","affiliation":[{"name":"Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China"},{"name":"Sichuan\u2013Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing 400065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Mei","family":"Hu","sequence":"additional","affiliation":[{"name":"Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China"},{"name":"Sichuan\u2013Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing 400065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5252-651X","authenticated-orcid":false,"given":"Wei-Han","family":"Qin","sequence":"additional","affiliation":[{"name":"Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China"},{"name":"Sichuan\u2013Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing 400065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1539-9192","authenticated-orcid":false,"given":"Sibao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong 999077, China"},{"name":"State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China"},{"name":"Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yang","sequence":"additional","affiliation":[{"name":"Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China"},{"name":"Sichuan\u2013Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing 400065, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3671-5257","authenticated-orcid":false,"given":"Guo-Qing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong 999077, China"},{"name":"State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China"},{"name":"Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cld.2022.08.004","article-title":"Hepatocellular carcinoma: New developments","volume":"27","author":"Ganesan","year":"2023","journal-title":"Clin. 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Evaluating the polarization of tumor-associated macrophages into M1 and M2 phenotypes in human cancer tissue: Technicalities and challenges in routine clinical practice. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01512"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13578-019-0342-7","article-title":"Macrophages and hepatocellular carcinoma","volume":"9","author":"Tian","year":"2019","journal-title":"Cell Biosci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Arvanitakis, K., Koletsa, T., Mitroulis, I., and Germanidis, G. (2022). Tumor-associated macrophages in hepatocellular carcinoma pathogenesis, prognosis and therapy. 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