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Epigenetic regulation, particularly histone modifications such as methylation, acetylation, phosphorylation, and lactylation, plays a pivotal role in orchestrating gene expression and tumor progression, representing promising yet complex therapeutic targets. Bioactive compounds derived from natural plants, characterized by multi\u2010target activity and low toxicity, have emerged as potent modulators of histone modifications, capable of influencing tumor growth, metastasis, and the tumor microenvironment. Here, we provide a comprehensive review of recent advances elucidating how natural products influence cancer progression and reshape the tumor immune microenvironment by regulating histone modifications. We integrate current knowledge of key histone marks, modifying enzymes, and signaling pathways, proposing a unified framework linking natural compounds, epigenetic regulation, and tumorigenesis. By uncovering these molecular mechanisms, we highlight that plant bioactive compounds can reshape the tumor immune microenvironment through histone modifications to inspire the development of novel, safer, and more effective anticancer agents.<\/jats:p>","DOI":"10.1002\/ptr.70386","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T06:01:13Z","timestamp":1779775273000},"page":"5208-5254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Plant Bioactives as Regulators of Histone Modifications: Bridging Epigenetics and Anticancer Therapy"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2313-0303","authenticated-orcid":false,"given":"Mengxiao","family":"Wang","sequence":"first","affiliation":[{"name":"Heilongjiang University of Chinese Medicine  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3011-5819","authenticated-orcid":false,"given":"Junyi","family":"Liang","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinping","family":"Zhu","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushuang","family":"Xing","sequence":"additional","affiliation":[{"name":"Graduate Department Qiqihar Medical University  Qiqihar Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijun","family":"Chang","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Medical Technology Qiqihar Medical College  Qiqihar China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-15-0119"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019521"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-024-02490-7"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2024.102422"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2024.106110"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2025.2551680"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2021.11881"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106487"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.70001"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.968398"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-024-10299-x"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-022-02989-7"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/6986445"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2020.113770"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2023.02.037"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlad016"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.06.020"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/13880209.2020.1738503"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02039-0"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24097872"},{"issue":"1","key":"e_1_2_11_23_1","first-page":"55","article-title":"Eglerisine, a Novel Sesquiterpenoid Tropolone From Dulacia Egleri With Antiproliferative Effect Against an Acute Myeloid Leukemia Lineage","volume":"86","author":"Novais L. 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