JMDSJournal of Medicines Development Sciences2382-63632382-6371Bio-Byword Scientific Publishing Pty. Ltd.10.26689/JMDS.v11i3.15976ArticleFlavonoids Targeting the PI3K/Akt/mTOR Pathway in Breast Cancer: A Systematic Reviewhttps://artdesignp.com/journal/JMDS/11/3/10.26689/JMDS.v11i3.15976HuangYin20261132026-09-16Background: The PI3K/Akt/mTOR pathway supports breast-cancer cell growth, survival and motility, and its persistent activation is associated with treatment resistance. Flavonoids are often described as multi-target natural compounds, but their activity against this pathway has not been synthesised consistently. Methods: PubMed, Scopus and Web of Science were searched to 23 March 2026 for peer-reviewed preclinical studies of single, naturally occurring flavonoids in human breast-cancer models. Ten studies published from 2021 to 2026 met the eligibility criteria. In vivo risk of bias was assessed with SYRCLE's tool, and in vitro reliability with an adapted ToxRTool. Results: The ten compounds were luteolin, sophoraflavanone G, eriodictyol, karanjin, calycosin, kushenol A, ampelopsin, ononin, galangin and tangeretin. Every study reported suppression of at least part of the PI3K/Akt/mTOR cascade, although only five measured all three core nodes. Reduced signalling generally coincided with lower proliferation, cell-cycle arrest or apoptosis; five studies also reported reduced migration or invasion, and seven included an animal experiment. Conclusions: The direction of effect was broadly consistent, but the evidence remains preclinical, heavily weighted towards MDA-MB-231 cells, and incomplete for pharmacokinetics, toxicity and pathway-wide target engagement.Breast cancer, Flavonoids, PI3K/Akt/mTOR, Apoptosis, Metastasis, Systematic review

[1] Wu HT, Lin J, Liu YE, et al., 2021, Luteolin Suppresses Androgen Receptor-Positive Triple-Negative Breast Cancer Cell Proliferation and Metastasis by Epigenetic Regulation of MMP9 Expression via the AKT/mTOR Signaling Pathway. Phytomedicine, 81: 153437. [2] Cheng W, Liu D, Guo M, et al., 2022, Sophoraflavanone G Suppresses the Progression of Triple-Negative Breast Cancer via the Inactivation of EGFR-PI3K-AKT Signaling. Drug Dev Res, 5: 1138–1151. [3] He J, Fu H, Li C, et al., 2022, Eriodictyol Inhibits Breast Carcinogenesis by Targeting circ_0007503 and Repressing PI3K/Akt Pathway. Phytomedicine, 102: 154159. [4] Yu J, Yang H, Lv C, et al., 2022, The Cytotoxicity of Karanjin Toward Breast Cancer Cells Is Involved in the PI3K/Akt Signaling Pathway. Drug Dev Res, 7: 1673–1682. [5] Li Y, Hu S, Chen Y, et al., 2023, Calycosin Inhibits Triple-Negative Breast Cancer Progression Through Down-Regulation of the Novel Estrogen Receptor-α Splice Variant ER-α30-Mediated PI3K/AKT Signaling Pathway. Phytomedicine, 118: 154924. [6] Liu T, Gong J, Lai G, et al., 2023, Flavonoid Extract Kushenol A Exhibits Anti-Proliferative Activity in Breast Cancer Cells via Suppression of PI3K/AKT/mTOR Pathway. Cancer Med, 2: 1643–1654. [7] Meng M, Yang Q, Ouyang Z, et al., 2023, Ampelopsin Induces MDA-MB-231 Cell Cycle Arrest Through Cyclin B1-Mediated PI3K/AKT/mTOR Pathway In Vitro and In Vivo. Acta Pharm, 1: 75–90. [8] Ganesan K, Xu C, Wu J, et al., 2024, Ononin Inhibits Triple-Negative Breast Cancer Lung Metastasis by Targeting the EGFR-Mediated PI3K/Akt/mTOR Pathway. Sci China Life Sci, 9: 1849–1866. [9] Nimal S, Kumbhar N, Pote MS, et al., 2025, Reversal of Epithelial to Mesenchymal Transition in Triple Negative Breast Cancer Through Epigenetic Modulations by Dietary Flavonoid Galangin and Its Combination with SAHA. Cell Commun Signal, 1: 163. [10] Reddy JS, Shankaraiah P, 2026, Tangeretin Suppresses HER2-Driven Breast Cancer via PI3K/AKT/mTOR Inhibition and Caspase-Dependent Apoptosis. Bangladesh J Pharmacol, 1: 1–10. [11] Page MJ, McKenzie JE, Bossuyt PM, et al., 2021, The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. BMJ, 372: n71. [12] Hooijmans CR, Rovers MM, de Vries RBM, et al., 2014, SYRCLE's Risk of Bias Tool for Animal Studies. BMC Med Res Methodol, 14: 43. [13] Schneider K, Schwarz M, Burkholder I, et al., 2009, "ToxRTool", A New Tool to Assess the Reliability of Toxicological Data. Toxicol Lett, 2: 138–144. [14] Glaviano A, Foo ASC, Lam HY, et al., 2023, PI3K/AKT/mTOR Signaling Transduction Pathway and Targeted Therapies in Cancer. Mol Cancer, 1: 138. [15] Xue C, Li G, Lu J, et al., 2021, Crosstalk Between circRNAs and the PI3K/AKT Signaling Pathway in Cancer Progression. Signal Transduct Target Ther, 1: 400. [16] Datta SR, Dudek H, Tao X, et al., 1997, Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery. Cell, 2: 231–241. [17] Grasset EM, Dunworth M, Sharma G, et al., 2022, Triple-Negative Breast Cancer Metastasis Involves Complex Epithelial-Mesenchymal Transition Dynamics and Requires Vimentin. Sci Transl Med, 656: eabn7571. [18] Yuan D, Guo Y, Pu F, et al., 2024, Opportunities and Challenges in Enhancing the Bioavailability and Bioactivity of Dietary Flavonoids: A Novel Delivery System Perspective. Food Chem, 430: 137115.