{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:38:27Z","timestamp":1785429507938,"version":"3.56.0"},"reference-count":99,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260530"],"award-info":[{"award-number":["82260530"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82260530"],"award-info":[{"award-number":["82260530"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009103","name":"Shaanxi Provincial Department of Education","doi-asserted-by":"publisher","award":["24JK0726"],"award-info":[{"award-number":["24JK0726"]}],"id":[{"id":"10.13039\/501100009103","id-type":"DOI","asserted-by":"publisher"}]},{"award":["24JK0726"],"award-info":[{"award-number":["24JK0726"]}],"id":[{"id":"https:\/\/ror.org\/00jb7xy46","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Yan\u2019an Key Research and Development Program Project","award":["2025SLSFGG-124"],"award-info":[{"award-number":["2025SLSFGG-124"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Hesperidin is a natural flavonoid derived from citrus plants, which can be hydrolyzed into hesperetin in vivo. Both compounds have anti-inflammatory, antioxidant and antitumor activities. At present, there is a lack of reviews focusing on the epigenetic regulation of cancer stem cells (CSCs) mediated by hesperidin and hesperetin. This review summarizes the molecular crosstalk between hesperidin\/hesperetin and CSCs mediated via three major epigenetic pathways, including direct regulatory effects, indirect modulatory actions, and mechanistic relationships proposed based on scientific hypotheses. We elaborate their effects on inhibiting the self-renewal, invasion and metastasis of CSCs as well as reversing chemoresistance, and analyze the crosstalk between epigenetic networks and classical signaling pathways of CSCs. Furthermore, we discuss the core bottlenecks restricting the clinical transformation of these two compounds and introduce improvement strategies such as nanodelivery systems. Current research is still confronted with problems including CSC heterogeneity and the potential off-target toxicity of drugs. In conclusion, hesperidin and hesperetin may serve as potential candidate agents for epigenetic regulation targeting CSCs, which can offer novel theoretical basis for comprehensive tumor therapy.<\/jats:p>","DOI":"10.3390\/biom16071063","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:14:27Z","timestamp":1784621667000},"page":"1063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hesperidin and Hesperetin: Epigenetic-Stemness Crosstalk, Antitumor Mechanisms, Preclinical Data and Translation Barriers"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2907-750X","authenticated-orcid":false,"given":"Mengqi","family":"Guo","sequence":"first","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linxin","family":"Shao","sequence":"additional","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Yin","sequence":"additional","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianrui","family":"Kou","sequence":"additional","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lele","family":"Shang","sequence":"additional","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Guan","sequence":"additional","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Li","sequence":"additional","affiliation":[{"name":"Yan\u2019an Medical College, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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