{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T06:37:00Z","timestamp":1776753420876,"version":"3.51.2"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Cervical cancer remains a major gynecological malignancy with a substantial global burden, particularly in low- and middle-income regions. Tumor angiogenesis driven by the VEGF\/DLL4\u2013Notch axis promotes cervical cancer progression, and the anti-VEGF antibody bevacizumab shows limited clinical benefit because of acquired resistance. Our prior work identified anti-tumor activity in the Xinjiang-native medicinal plant\n                    <jats:italic>Ferula songorica<\/jats:italic>\n                    Pall. ex Spreng, but the effects and mechanisms of its principal bioactive metabolite, akiferidin, in cervical cancer have not been defined. Here, we evaluated akiferidin\u2019s anti-tumor and anti-angiogenic activities in cervical cancer, examined its combinatorial potential with bevacizumab, and explored the underlying mechanisms. We developed and validated an HPLC method to quantify akiferidin in\n                    <jats:italic>F. songorica<\/jats:italic>\n                    ethanol extract.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , we used MTT, wound-healing, Transwell, and Matrigel tube-formation assays to assess akiferidin\u2019s effects on U14 cell proliferation, migration, invasion, and HUVEC angiogenesis.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , we evaluated the efficacy and safety of akiferidin alone and in combination with bevacizumab in U14 xenograft-bearing C57BL\/6 mice. Modulation of the VEGF\/DLL4\u2013Notch pathway was examined by IHC and Western blot, and direct binding between akiferidin and VEGF-A was investigated by molecular docking followed by 100\u00a0ns molecular dynamics simulation. The HPLC method demonstrated excellent robustness (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 0.999, all RSD&amp;lt;2%), yielding an akiferidin content of 57.45 \u00b1 1.42\u00a0mg\/g in the extract.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , akiferidin inhibited U14 cell proliferation, migration, invasion, and HUVEC tube formation in a concentration-dependent manner (IC\n                    <jats:sub>50<\/jats:sub>\n                    = 8.06\u00a0\u03bcg\/mL).\n                    <jats:italic>In vivo<\/jats:italic>\n                    , akiferidin suppressed tumor growth in a dose-dependent fashion without overt systemic toxicity, and its combination with bevacizumab markedly enhanced antitumor efficacy while reducing tumor microvessel density. Mechanistically, akiferidin significantly downregulated key proteins in the VEGF\/DLL4-Notch pathway, with greater inhibition observed in the combination group. Molecular docking and dynamics confirmed stable binding between akiferidin and VEGF-A at five key sites. In conclusion, akiferidin exerts potent anti\u2013cervical cancer activity by inhibiting angiogenesis through modulation of the VEGF\/DLL4-Notch pathway, and its combination with bevacizumab enhances antitumor efficacy with favorable\n                    <jats:italic>in vivo<\/jats:italic>\n                    safety, representing a promising therapeutic strategy for cervical cancer.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1803135","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:37:18Z","timestamp":1776749838000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Akiferidin suppresses cervical cancer growth and angiogenesis via the VEGF\/DLL4-Notch pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingyuan","family":"Lan","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Zhejiang Provincial Clinical Research Center for Gynecological Diseases, The Second Affiliated Hospital of Wenzhou Medical University","place":["Wenzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Processing and Research of Traditional Chinese Medicine","place":["Urumqi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuerhong","family":"Dina","sequence":"additional","affiliation":[{"name":"Office of Drug Clinical Trial Institution, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University","place":["Urumqi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University","place":["Urumqi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dexi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University","place":["Urumqi, China"]},{"name":"Xinjiang Key Laboratory of Processing and Research of Traditional Chinese Medicine","place":["Urumqi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Office of Drug Clinical Trial Institution, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University","place":["Urumqi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"114705","DOI":"10.1016\/j.intimp.2025.114705","article-title":"Encapsulation of Ferula-derived bioactive compounds in nanoparticles: a promising therapeutic route for cancers and infectious diseases","volume":"157","author":"Aghaali","year":"2025","journal-title":"Int. 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