{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:37:25Z","timestamp":1787791045337,"version":"build-2784847793"},"reference-count":83,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Misr University for Science & Technology"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Complement Med Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. The therapeutic efficacy of conventional chemotherapeutic agents such as doxorubicin (DOX) is limited by dose-dependent toxicity and the development of drug resistance. Combination strategies incorporating bioactive natural products may enhance anticancer efficacy while enabling dose reduction. The present study aimed to evaluate the potential synergistic cytotoxicity of combining Fenugreek aqueous extract (FAE) with (DOX) against the HepG2 cell line.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Phytochemical characterization was performed using\n                      <jats:italic>UHPLC-QTOF-MS\/MS Profiling<\/jats:italic>\n                      and HPLC. Cell viability and selectivity were assessed using the SRB assay. Apoptosis, necrosis, autophagy, and cell cycle distribution were analysed by flow cytometry and Western blotting. Drug\u2013drug interaction was evaluated using the Chou\u2013Talalay method. Molecular docking was performed to explore potential interactions between selected FAE constituents and apoptosis- and autophagy-related protein targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FAE enhanced DOX\u2019s cytotoxicity on HepG2 cells, with the interaction ranging from synergistic to additive depending on the concentration ratio. The DOX\/FAE combination enhanced cell death through sub-G1 arrest and augmented apoptotic, necrotic, and autophagic responses compared with monotherapies. Western blot analysis demonstrated modulation of the Bax\/Bcl-2 ratio and increased LC3-II expression. Docking simulations suggested favourable binding of selected steroidal saponins to Bcl-2 and LC3 proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings indicate that FAE potentiates DOX-induced cytotoxicity in vitro through modulation of multiple regulated cell death pathways. While the results support the possibility of this combination as a dose-modulating strategy, further validation in additional HCC models and in vivo systems is required.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12906-026-05386-3","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T06:00:28Z","timestamp":1778047228000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fenugreek seed extract\u2013doxorubicin synergy against hepatocellular carcinoma in HepG2 cells: in vitro and in silico mechanistic studies"],"prefix":"10.1186","volume":"26","author":[{"given":"Wesam","family":"Ragab","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Mahmoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasha M.","family":"Allam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesam S.","family":"Qayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama M.","family":"Gomaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seham S.","family":"El-Hawary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer S.","family":"Moawad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabab","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"issue":"7","key":"5386_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/diseases13070207","volume":"13","author":"N Amin","year":"2025","unstructured":"Amin N, Anwar J, Sulaiman A, Naumova NN, Anwar N. Hepatocellular carcinoma: a comprehensive review. Diseases. 2025;13(7):207.","journal-title":"Diseases"},{"key":"5386_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2025.101571","author":"E Mauro","year":"2025","unstructured":"Mauro E, de Castro T, Zeitlhoefler M, Sung MW, Villanueva A, Mazzaferro V, et al. Hepatocellular carcinoma: epidemiology, diagnosis and treatment. JHEP Rep. 2025:101571. https:\/\/doi.org\/10.1016\/j.jhepr.2025.101571","journal-title":"JHEP Rep"},{"key":"5386_CR3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1526206","volume":"15","author":"Z Ding","year":"2025","unstructured":"Ding Z, Wang L, Sun J, Zheng L, Tang Y, Tang H. Hepatocellular carcinoma: pathogenesis, molecular mechanisms, and treatment advances. Front Oncol. 2025;15:1526206.","journal-title":"Front Oncol"},{"issue":"1","key":"5386_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02075-w","volume":"10","author":"J Zheng","year":"2025","unstructured":"Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, et al. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther. 2025;10(1):35.","journal-title":"Signal Transduct Target Ther"},{"issue":"2","key":"5386_CR5","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2902052","volume":"29","author":"Y-R Lei","year":"2024","unstructured":"Lei Y-R, He X-l, Li J, Mo C-f. Drug resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Front Biosci Landmark Ed. 2024;29(2):52.","journal-title":"Front Biosci Landmark Ed"},{"key":"5386_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpta.2025.100992","author":"J Sun","year":"2025","unstructured":"Sun J, Yu H, Badehnoosh B. Engineering chitosan nanoparticles for targeted doxorubicin delivery in liver cancer: a mechanistic and preclinical review. Carbohydr Polym Technol Appl. 2025:100992. https:\/\/doi.org\/10.1016\/j.carpta.2025.100992","journal-title":"Carbohydr Polym Technol Appl"},{"key":"5386_CR7","doi-asserted-by":"crossref","unstructured":"Shukla PK, Dallio M, Chemello L. Hepatocellular carcinoma: from diagnostic approaches to surgical and systemic therapies. Frontiers; 2025. p. 1633587.","DOI":"10.3389\/fmed.2025.1633587"},{"issue":"11","key":"5386_CR8","doi-asserted-by":"publisher","DOI":"10.3390\/nu16111642","volume":"16","author":"J Guo","year":"2024","unstructured":"Guo J, Yan W, Duan H, Wang D, Zhou Y, Feng D, et al. Therapeutic effects of natural products on liver cancer and their potential mechanisms. Nutrients. 2024;16(11):1642.","journal-title":"Nutrients"},{"key":"5386_CR9","doi-asserted-by":"publisher","DOI":"10.32604\/biocell.2024.050396","author":"L Zhang","year":"2024","unstructured":"Zhang L, Li Y, Mao J. Research progress on natural products against hepatocellular carcinoma. Biocell. 2024. https:\/\/doi.org\/10.32604\/biocell.2024.050396.","journal-title":"Biocell"},{"issue":"6","key":"5386_CR10","doi-asserted-by":"publisher","DOI":"10.3390\/foods14060933","volume":"14","author":"R Ahmad","year":"2025","unstructured":"Ahmad R, Alqathama A, Al-Maimani R, Al-Said HM, Ashgar SS, Althubiti M, et al. Exploring the role of phytochemical classes in the biological activities of fenugreek (Trigonella feonum graecum): a comprehensive analysis based on statistical evaluation. Foods. 2025;14(6):933.","journal-title":"Foods"},{"issue":"11","key":"5386_CR11","doi-asserted-by":"publisher","DOI":"10.3390\/plants11111450","volume":"11","author":"T Visuvanathan","year":"2022","unstructured":"Visuvanathan T, Than LTL, Stanslas J, Chew SY, Vellasamy S. Revisiting Trigonella foenum-graecum L.: pharmacology and therapeutic potentialities. Plants. 2022;11(11):1450.","journal-title":"Plants"},{"key":"5386_CR12","doi-asserted-by":"publisher","DOI":"10.1016\/j.scenv.2025.100252","author":"T Adhikary","year":"2025","unstructured":"Adhikary T, Tripathi G, Majumdar A, Basak P. Highlighting phytoconstituents of Trigonella foenum-graecum (fenugreek) seeds as multi-targeted inhibitors of common cancer receptors and subsequently optimizing its sequential extraction to develop an oral nutraceutical. Sustain Chem Environ. 2025:100252. https:\/\/doi.org\/10.1016\/j.scenv.2025.100252","journal-title":"Sustain Chem Environ"},{"issue":"2","key":"5386_CR13","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.canlet.2009.12.003","volume":"292","author":"F Li","year":"2010","unstructured":"Li F, Fernandez PP, Rajendran P, Hui KM, Sethi G. Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells. Cancer Lett. 2010;292(2):197\u2013207.","journal-title":"Cancer Lett"},{"issue":"1","key":"5386_CR14","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6882-14-114","volume":"14","author":"A Alsemari","year":"2014","unstructured":"Alsemari A, Alkhodairy F, Aldakan A, Al-Mohanna M, Bahoush E, Shinwari Z, et al. The selective cytotoxic anti-cancer properties and proteomic analysis of Trigonella foenum-graecum. BMC Complement Altern Med. 2014;14(1):114.","journal-title":"BMC Complement Altern Med"},{"issue":"1","key":"5386_CR15","first-page":"914645","volume":"2015","author":"MI Khalil","year":"2015","unstructured":"Khalil MI, Ibrahim MM, El-Gaaly GA, Sultan AS. Trigonella foenum (Fenugreek) induced apoptosis in hepatocellular carcinoma cell line, HepG2, mediated by upregulation of p53 and proliferating cell nuclear antigen. BioMed Res Int. 2015;2015(1):914645\u2013914645.","journal-title":"BioMed Res Int"},{"issue":"3","key":"5386_CR16","doi-asserted-by":"publisher","first-page":"458","DOI":"10.3390\/cancers18030458","volume":"18","author":"M Vittal","year":"2026","unstructured":"Vittal M, Menegassi B, Vinciguerra M. Risks, benefits, and molecular targets of fenugreek administration in the treatment of hepatocellular carcinoma. Cancers. 2026;18(3):458\u2013458.","journal-title":"Cancers"},{"issue":"39","key":"5386_CR17","doi-asserted-by":"publisher","first-page":"32057","DOI":"10.1039\/D5RA02005K","volume":"15","author":"EM Abdelmalek","year":"2025","unstructured":"Abdelmalek EM, Malak LG, Qayed WS, Ahmed MA. Insights into LSD1 and quorum sensing inhibitory potential of phytoconstituents isolated from Ardisia elliptica Thunb aerial parts. RSC Adv. 2025;15(39):32057\u201370.","journal-title":"RSC Adv"},{"issue":"2","key":"5386_CR18","doi-asserted-by":"publisher","first-page":"936","DOI":"10.3390\/cimb45020060","volume":"45","author":"SGA Salam","year":"2023","unstructured":"Salam SGA, Rashed MM, Ibrahim NA, Rahim EAA, Alsufiani HM, Mansouri RA, et al. Cell growth inhibition, DNA fragmentation and apoptosis-inducing properties of household-processed leaves and seeds of fenugreek (Trigonella foenum-graecum Linn.) against HepG2, HCT-116, and MCF-7 cancerous cell lines. Curr Issues Mol Biol. 2023;45(2):936\u201353.","journal-title":"Curr Issues Mol Biol"},{"key":"5386_CR19","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S300025","author":"FA Alrumaihi","year":"2021","unstructured":"Alrumaihi FA, Khan MA, Allemailem KS, Alsahli MA, Almatroudi A, Younus H, et al. Methanolic fenugreek seed extract induces p53-dependent mitotic catastrophe in breast cancer cells, leading to apoptosis. J Inflamm Res. 2021Apr 16:1511-35. https:\/\/doi.org\/10.2147\/JIR.S300025","journal-title":"J Inflamm Res"},{"issue":"12","key":"5386_CR20","doi-asserted-by":"publisher","first-page":"e14005","DOI":"10.1111\/jfbc.14005","volume":"45","author":"P Arya","year":"2021","unstructured":"Arya P, Kumar P. Diosgenin a steroidal compound: an emerging way to cancer management. J Food Biochem. 2021;45(12):e14005.","journal-title":"J Food Biochem"},{"key":"5386_CR21","first-page":"58","volume":"333","author":"P Molina-S\u00e1nchez","year":"2019","unstructured":"Molina-S\u00e1nchez P, Lujambio A. Experimental models for preclinical research in hepatocellular carcinoma. Hepatocellular carcinoma: translational precision Med approaches. 2019;333:58.","journal-title":"Hepatocellular carcinoma: translational precision Med approaches"},{"issue":"3","key":"5386_CR22","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.3390\/molecules27031117","volume":"27","author":"ME Hussein","year":"2022","unstructured":"Hussein ME, Mohamed OG, El-Fishawy AM, El-Askary HI, El-Senousy AS, El-Beih AA, et al. Identification of antibacterial metabolites from endophytic fungus Aspergillus fumigatus, isolated from Albizia lucidior leaves (Fabaceae), utilizing metabolomic and molecular docking techniques. Molecules. 2022;27(3):1117.","journal-title":"Molecules"},{"key":"5386_CR23","first-page":"12","volume":"45","author":"PD H","year":"2008","unstructured":"H PD, Faria M. HPLC fingerprinting of fenugreek seeds using trigonelline as a biomarker. Indian Drugs. 2008;45:12\u201312.","journal-title":"Indian Drugs"},{"issue":"1","key":"5386_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-97395-4","volume":"15","author":"RM Allam","year":"2025","unstructured":"Allam RM, El-Nasr NMA, El baset MA, Saleh DO, El-Seidy AM. Unveiling the potency of ZnO and CuO nanocomposites in combating hepatocellular carcinoma by inducing cell death and suppressing migration. Sci Rep. 2025;15(1):15477.","journal-title":"Sci Rep"},{"key":"5386_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2025.106980","author":"AM Mousa","year":"2025","unstructured":"Mousa AM, Abdelraof M, Allam R. Marine L-arginase encapsulated in poly (lactic-co-glycolic acid) nanoparticles: a novel anti-cancer strategy for effective hepatocellular carcinoma treatment in vitro and in vivo. J Drug Deliv Sci Technol. 2025. https:\/\/doi.org\/10.1016\/j.jddst.2025.106980.","journal-title":"J Drug Deliv Sci Technol"},{"issue":"3","key":"5386_CR26","first-page":"720","volume":"21","author":"T Artun","year":"2016","unstructured":"Artun T, Karagoz A, Ozcan G, Melikoglu G, Anil S, Kultur S, et al. In vitro anticancer and cytotoxic activities of some plant extracts on HeLa and Vero cell lines. J BUON. 2016;21(3):720\u20135.","journal-title":"J BUON"},{"issue":"3","key":"5386_CR27","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1124\/pr.58.3.10","volume":"58","author":"T-C Chou","year":"2006","unstructured":"Chou T-C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58(3):621\u201381.","journal-title":"Pharmacol Rev"},{"key":"5386_CR28","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.sajb.2025.05.025","volume":"183","author":"HA Mokbel","year":"2025","unstructured":"Mokbel HA, El Hawary SS, Allam RM, Eldesoky AH, El-Halawany AM, El-Motayam AK. Cytotoxic and anti-migration effects of cardiac glycosides from Gomphocarpus fruticosus and Kanahia laniflora on hepatocellular carcinoma; LC-MS\/MS profiling, in vitro bioassay and molecular docking study. S Afr J Bot. 2025;183:243\u201364.","journal-title":"S Afr J Bot"},{"issue":"1","key":"5386_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s12906-023-04113-6","volume":"23","author":"K Shari","year":"2023","unstructured":"Shari K, El Gedaily RA, Allam RM, Meselhy KM, Khaleel AE, Abdel-Sattar E. Jatrophone: a cytotoxic macrocylic diterpene targeting PI3K\/AKT\/NF-\u03baB pathway, inducing apoptosis and autophagy in resistant breast cancer cells. BMC Complement Med Ther. 2023;23(1):293.","journal-title":"BMC Complement Med Ther"},{"issue":"12","key":"5386_CR30","doi-asserted-by":"publisher","DOI":"10.3390\/nu17121993","volume":"17","author":"HAM El baghdady","year":"2025","unstructured":"El baghdady HAM, Allam RM, Darwish MI, Hammad MO, Fadel HH, Ghoneum MH. Protective effect of Biobran\/MGN-3, an arabinoxylan from rice bran, against the cytotoxic effects of polyethylene nanoplastics in normal mouse hepatocytes: an in vitro and in silico study. Nutrients. 2025;17(12):1993.","journal-title":"Nutrients"},{"key":"5386_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00633","volume":"8","author":"SS Varankar","year":"2018","unstructured":"Varankar SS, Bapat SA. Migratory metrics of wound healing: a quantification approach for in vitro scratch assays. Front Oncol. 2018;8:633.","journal-title":"Front Oncol"},{"issue":"31","key":"5386_CR32","doi-asserted-by":"publisher","first-page":"28563","DOI":"10.1021\/acsomega.3c02953","volume":"8","author":"OE Abdel-Sattar","year":"2023","unstructured":"Abdel-Sattar OE, Allam RM, Al-Abd AM, El-Halawany AM, El-Desoky AM, Mohamed SO, et al. Hypophyllanthin and phyllanthin from Phyllanthus niruri synergize doxorubicin anticancer properties against resistant breast cancer cells. ACS Omega. 2023;8(31):28563\u201376.","journal-title":"ACS Omega"},{"key":"5386_CR33","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.phymed.2017.10.006","volume":"36","author":"J Li","year":"2017","unstructured":"Li J, Zhang J, Zou L, Lee S-Y, Yang C, Seto S-W, et al. Pro-angiogenic effects of Ilexsaponin A1 on human umbilical vein endothelial cells in vitro and zebrafish in vivo. Phytomedicine. 2017;36:229\u201337.","journal-title":"Phytomedicine"},{"issue":"1","key":"5386_CR34","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.jfca.2014.04.002","volume":"35","author":"Z Benayad","year":"2014","unstructured":"Benayad Z, G\u00f3mez-Cordov\u00e9s C, Es-Safi NE. Identification and quantification of flavonoid glycosides from fenugreek (Trigonella foenum-graecum) germinated seeds by LC\u2013DAD\u2013ESI\/MS analysis. J Food Compos Anal. 2014;35(1):21\u20139.","journal-title":"J Food Compos Anal"},{"issue":"28","key":"5386_CR35","doi-asserted-by":"publisher","first-page":"8065","DOI":"10.1007\/s00216-016-9910-4","volume":"408","author":"MA Farag","year":"2016","unstructured":"Farag MA, Rasheed DM, Kropf M, Heiss AG. Metabolite profiling in Trigonella seeds via UPLC-MS and GC-MS analyzed using multivariate data analyses. Anal Bioanal Chem. 2016;408(28):8065\u201378.","journal-title":"Anal Bioanal Chem"},{"key":"5386_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.fbio.2020.100800","author":"MA Farag","year":"2021","unstructured":"Farag MA, Sharaf El-Din MG, Aboul-Fotouh Selim M, Owis AI, Abouzid SF. Mass spectrometry-based metabolites profiling of nutrients and anti-nutrients in major legume sprouts. Food Biosci. 2021;39. https:\/\/doi.org\/10.1016\/j.fbio.2020.100800","journal-title":"Food Biosci"},{"key":"5386_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodres.2022.112347","volume":"164","author":"S Gonda","year":"2023","unstructured":"Gonda S, Szucs Z, Plaszko T, Cziaky Z, Kiss-Szikszai A, Sinka D, et al. Quality-controlled LC-ESI-MS food metabolomics of fenugreek (Trigonella foenum-graecum) sprouts: insights into changes in primary and specialized metabolites. Food Res Int. 2023;164:112347.","journal-title":"Food Res Int"},{"key":"5386_CR38","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.jpba.2012.11.005","volume":"74","author":"LP Kang","year":"2013","unstructured":"Kang LP, Zhao Y, Pang X, Yu HS, Xiong CQ, Zhang J, et al. Characterization and identification of steroidal saponins from the seeds of Trigonella foenum-graecum by ultra high-performance liquid chromatography and hybrid time-of-flight mass spectrometry. J Pharm Biomed Anal. 2013;74:257\u201367.","journal-title":"J Pharm Biomed Anal"},{"issue":"2","key":"5386_CR39","doi-asserted-by":"publisher","first-page":"145","DOI":"10.24193\/subbchem.2017.2.11","volume":"62","author":"S V\u00edgh","year":"2017","unstructured":"V\u00edgh S, Czi\u00e1ky Z, Sinka LT, Pribac C, Mo\u015f L, Turcu\u015f V, et al. Analysis of Phytoconstituent Profile of Fenugreek \u2013 Trigonella Foenuem-Graecum L. \u2013 Seed Extracts. Studia Universitatis Babe\u0219-Bolyai Chem. 2017;62(2):145\u201366.","journal-title":"Studia Universitatis Babe\u0219-Bolyai Chem"},{"key":"5386_CR40","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1007\/s11418-010-0407-8","volume":"64","author":"G-R Wang","year":"2010","unstructured":"Wang G-R, Tang W-Z, Yao Q-Q, Zhong H, Liu Y-J. New flavonoids with 2BS cell proliferation promoting effect from the seeds of Trigonella foenum-graecum L. J Nat Med. 2010Jul;64(3):358-61.","journal-title":"J Nat Med"},{"issue":"5","key":"5386_CR41","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1007\/s40242-017-7136-4","volume":"33","author":"J Wang","year":"2017","unstructured":"Wang J, Jiang W, Liu Z, Wang J, Fu T, Wang Y. Analysis and identification of chemical constituents of fenugreek by UPLC-IT-MS n and UPLC-Q-TOF-MS. Chem Res Chin Univ. 2017;33(5):721\u201330.","journal-title":"Chem Res Chin Univ"},{"key":"5386_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.indcrop.2022.115595","volume":"188","author":"J Xiao","year":"2022","unstructured":"Xiao J, Bai H, Wang Q, Wang H, Yizimu H, Wu H, et al. Qualitative profiling and relative quantitative analysis of compounds in light-harvested and shading-treated sumac (Toxicodendron vernicifluum) leaves and their antibacterial activity. Ind Crops Prod. 2022;188:115595.","journal-title":"Ind Crops Prod"},{"key":"5386_CR43","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.talanta.2012.05.042","volume":"99","author":"B Abad-Garc\u00eda","year":"2012","unstructured":"Abad-Garc\u00eda B, Garmon-Lobato S, Berrueta LA, Gallo B, Vicente F. On line characterization of 58 phenolic compounds in Citrus fruit juices from Spanish cultivars by high-performance liquid chromatography with photodiode-array detection coupled to electrospray ionization triple quadrupole mass spectrometry. Talanta. 2012;99:213\u201324.","journal-title":"Talanta"},{"issue":"13","key":"5386_CR44","doi-asserted-by":"publisher","DOI":"10.3390\/molecules29132953","volume":"29","author":"T Du","year":"2024","unstructured":"Du T, Wang Y, Xie H, Liang D, Gao S. Fragmentation patterns of phenolic C-glycosides in mass spectrometry analysis. Molecules. 2024;29(13):2953.","journal-title":"Molecules"},{"issue":"8","key":"5386_CR45","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.apjtm.2015.07.012","volume":"8","author":"D-F Zhang","year":"2015","unstructured":"Zhang D-F, Zhang F, Zhang J, Zhang R-M, Li R. Protection effect of trigonelline on liver of rats with non-alcoholic fatty liver diseases. Asian Pac J Trop Med. 2015;8(8):651\u20134.","journal-title":"Asian Pac J Trop Med"},{"key":"5386_CR46","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.fct.2018.09.011","volume":"121","author":"L Sharma","year":"2018","unstructured":"Sharma L, Lone NA, Knott RM, Hassan A, Abdullah T. Trigonelline prevents high cholesterol and high fat diet induced hepatic lipid accumulation and lipo-toxicity in C57BL\/6J mice, via restoration of hepatic autophagy. Food Chem Toxicol. 2018;121:283\u201396.","journal-title":"Food Chem Toxicol"},{"issue":"1","key":"5386_CR47","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1186\/s12906-023-04046-0","volume":"23","author":"MS Abdelrahim","year":"2023","unstructured":"Abdelrahim MS, Abdel-Baky AM, Bayoumi SA, Mohamed SM, Abdel-Mageed WM, Backheet EY. Cytotoxic flavone-C-glycosides from the leaves of Dypsis pembana (HE Moore) Beentje & J. Dransf., Arecaceae: in vitro and molecular docking studies. BMC Complement Med Ther. 2023;23(1):214.","journal-title":"BMC Complement Med Ther"},{"key":"5386_CR48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jff.2020.103921","volume":"69","author":"G Huang","year":"2020","unstructured":"Huang G, Li S, Zhang Y, Zhou X, Chen W. Vicenin-2 is a novel inhibitor of STAT3 signaling pathway in human hepatocellular carcinoma. J Funct Foods. 2020;69:103921.","journal-title":"J Funct Foods"},{"issue":"4","key":"5386_CR49","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/j.bbrc.2018.01.111","volume":"496","author":"S-X Lv","year":"2018","unstructured":"Lv S-X, Qiao X. Isovitexin (IV) induces apoptosis and autophagy in liver cancer cells through endoplasmic reticulum stress. Biochem Biophys Res Commun. 2018;496(4):1047\u201354.","journal-title":"Biochem Biophys Res Commun"},{"issue":"14","key":"5386_CR50","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.2174\/1871520620666200424123139","volume":"20","author":"C Xu","year":"2020","unstructured":"Xu C, Cao X, Cao X, Liu L, Qiu Y, Li X, et al. Isovitexin inhibits stemness and induces apoptosis in hepatocellular carcinoma SK-Hep-1 spheroids by upregulating miR-34a expression. Anti-Cancer Agents in Medicinal Chemistry. 2020;20(14):1654\u201363.","journal-title":"Anti-Cancer Agents in Medicinal Chemistry"},{"issue":"10","key":"5386_CR51","doi-asserted-by":"publisher","first-page":"2519","DOI":"10.1007\/s00210-023-02472-y","volume":"396","author":"J-Y Tao","year":"2023","unstructured":"Tao J-Y, Li J, Wan L, Dong B-Z, Yu Y-J, Liu Y-M, et al. Orientin regulates the proliferation and migration of hepatocellular carcinoma cells. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(10):2519\u201328.","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"issue":"23","key":"5386_CR52","doi-asserted-by":"publisher","first-page":"5390","DOI":"10.1021\/jf500903g","volume":"62","author":"L Yuan","year":"2014","unstructured":"Yuan L, Wei S, Wang J, Liu X. Isoorientin induces apoptosis and autophagy simultaneously by reactive oxygen species (ROS)-related p53, PI3K\/Akt, JNK, and p38 signaling pathways in HepG2 cancer cells. J Agric Food Chem. 2014;62(23):5390\u2013400.","journal-title":"J Agric Food Chem"},{"issue":"51","key":"5386_CR53","doi-asserted-by":"publisher","first-page":"84520","DOI":"10.18632\/oncotarget.11731","volume":"7","author":"J-D He","year":"2016","unstructured":"He J-D, Wang Z, Li S-P, Xu Y-J, Yu Y, Ding Y-J, et al. Vitexin suppresses autophagy to induce apoptosis in hepatocellular carcinoma via activation of the JNK signaling pathway. Oncotarget. 2016;7(51):84520.","journal-title":"Oncotarget"},{"issue":"sup1","key":"5386_CR54","doi-asserted-by":"publisher","first-page":"S29","DOI":"10.1080\/10408398.2015.1067595","volume":"56","author":"J Xiao","year":"2016","unstructured":"Xiao J, Capanoglu E, Jassbi AR, Miron A. Advance on the flavonoid C-glycosides and health benefits. Crit Rev Food Sci Nutr. 2016;56(sup1):S29\u201345.","journal-title":"Crit Rev Food Sci Nutr"},{"issue":"15","key":"5386_CR55","doi-asserted-by":"publisher","first-page":"3900","DOI":"10.3390\/cancers15153900","volume":"15","author":"S Bouabdallah","year":"2023","unstructured":"Bouabdallah S, Al-Maktoum A, Amin A. Steroidal saponins: naturally occurring compounds as inhibitors of the hallmarks of cancer. Cancers. 2023;15(15):3900.","journal-title":"Cancers"},{"issue":"2","key":"5386_CR56","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.canlet.2009.12.003","volume":"292","author":"F Li","year":"2010","unstructured":"Li F, Fernandez PP, Rajendran P, Hui KM, Sethi G. Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells. Cancer Lett. 2010;292(2):197\u2013207.","journal-title":"Cancer Lett"},{"issue":"41","key":"5386_CR57","doi-asserted-by":"publisher","first-page":"11428","DOI":"10.1021\/acs.jafc.9b05131","volume":"67","author":"X Meng","year":"2019","unstructured":"Meng X, Dong H, Pan Y, Ma L, Liu C, Man S, Gao W. Diosgenyl saponin inducing endoplasmic reticulum stress and mitochondria-mediated apoptotic pathways in liver cancer cells. J Agric Food Chem. 2019;67(41):11428\u201335.","journal-title":"J Agric Food Chem"},{"key":"5386_CR58","doi-asserted-by":"publisher","first-page":"101946","DOI":"10.1016\/j.tranon.2024.101946","volume":"45","author":"F Jalali","year":"2024","unstructured":"Jalali F, Fakhari F, Sepehr A, Zafari J, Sarajar BO, Sarihi P, Jafarzadeh E. Synergistic anticancer effects of doxorubicin and metformin combination therapy: A systematic review. Translational Oncol. 2024;45:101946.","journal-title":"Translational Oncol"},{"key":"5386_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153408","volume":"81","author":"J Shi","year":"2021","unstructured":"Shi J, Li J, Li J, Li R, Wu X, Gao F, et al. Synergistic breast cancer suppression efficacy of doxorubicin by combination with glycyrrhetinic acid as an angiogenesis inhibitor. Phytomedicine. 2021;81:153408.","journal-title":"Phytomedicine"},{"issue":"2","key":"5386_CR60","doi-asserted-by":"publisher","DOI":"10.62347\/PGLT6191","volume":"17","author":"NAAB Morshidi","year":"2025","unstructured":"Morshidi NAAB, Uddin MS, Lee J, Han S-I, Kim J-H. Anticancer activity of Trigonella Foenumgraecum (fenugreek) seed extract by inducing apoptosis in pancreatic cancer cell. Am J Transl Res. 2025;17(2):832.","journal-title":"Am J Transl Res"},{"issue":"10","key":"5386_CR61","doi-asserted-by":"publisher","first-page":"5783","DOI":"10.7314\/APJCP.2013.14.10.5783","volume":"14","author":"AA Alshatwi","year":"2013","unstructured":"Alshatwi AA, Shafi G, Hasan TN, Syed NA, Khoja KK. Fenugreek induced apoptosis in breast cancer MCF-7 cells mediated independently by Fas receptor change. Asian Pac J Cancer Prev. 2013;14(10):5783\u20138.","journal-title":"Asian Pac J Cancer Prev"},{"key":"5386_CR62","unstructured":"ALKA\u00c7 B\u00c7, AYNA TK, PEHL\u0130VAN M, SOY\u00d6Z M. P\u0130R\u0130M \u0130. Anticancer Effects of Fenugreek and Cinnamon Extracts in Combination with Doxorubicin and Cisplatin on U87 Glioblastoma Cell Line. Forbes J Med. 2025;6(1):41\u201350."},{"key":"5386_CR63","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.985363","volume":"12","author":"S Qian","year":"2022","unstructured":"Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J. The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front Oncol. 2022;12:985363.","journal-title":"Front Oncol"},{"issue":"18","key":"5386_CR64","doi-asserted-by":"publisher","first-page":"3494","DOI":"10.1111\/j.1742-4658.2011.08271.x","volume":"278","author":"I Manov","year":"2011","unstructured":"Manov I, Pollak Y, Broneshter R, Iancu TC. Inhibition of doxorubicin-induced autophagy in hepatocellular carcinoma Hep3B cells by sorafenib\u2013the role of extracellular signal\u2010regulated kinase counteraction. FEBS J. 2011;278(18):3494\u2013507.","journal-title":"FEBS J"},{"issue":"11","key":"5386_CR65","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/s41419-019-2053-8","volume":"10","author":"Y Zhou","year":"2019","unstructured":"Zhou Y, Chen E, Tang Y, Mao J, Shen J, Zheng X, et al. miR-223 overexpression inhibits doxorubicin-induced autophagy by targeting FOXO3a and reverses chemoresistance in hepatocellular carcinoma cells. Cell Death Dis. 2019;10(11):843.","journal-title":"Cell Death Dis"},{"key":"5386_CR66","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1472-6882-12-202","volume":"12","author":"NM Al-Daghri","year":"2012","unstructured":"Al-Daghri NM, Alokail MS, Alkharfy KM, Mohammed AK, Abd-Alrahman SH, Yakout SM, et al. Fenugreek extract as an inducer of cellular death via autophagy in human T lymphoma Jurkat cells. BMC Complement Altern Med. 2012;12:1\u20138.","journal-title":"BMC Complement Altern Med"},{"issue":"14","key":"5386_CR67","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1002\/1873-3468.14372","volume":"596","author":"S Saurav","year":"2022","unstructured":"Saurav S, Manna SK. Profilin upregulation induces autophagy through stabilization of AMP-activated protein kinase. FEBS Lett. 2022;596(14):1765\u201377.","journal-title":"FEBS Lett"},{"key":"5386_CR68","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/914645","volume":"2015","author":"MI Khalil","year":"2015","unstructured":"Khalil MI, Ibrahim MM, El-Gaaly GA, Sultan AS. Trigonella foenum (Fenugreek) induced apoptosis in hepatocellular carcinoma cell line, HepG2, mediated by upregulation of p53 and proliferating cell nuclear antigen. BioMed Res Int. 2015;2015:914645.","journal-title":"BioMed Res Int"},{"key":"5386_CR69","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.biopha.2017.03.071","volume":"90","author":"K El Bairi","year":"2017","unstructured":"El Bairi K, Ouzir M, Agnieszka N, Khalki L. Anticancer potential of Trigonella foenum graecum: cellular and molecular targets. Biomed Pharmacother. 2017;90:479\u201391.","journal-title":"Biomed Pharmacother"},{"issue":"9","key":"5386_CR70","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/iub.2772","volume":"75","author":"MG Lee","year":"2023","unstructured":"Lee MG, Lee KS, Nam KS. Combined doxorubicin and arctigenin treatment induce cell cycle arrest-associated cell death by promoting doxorubicin uptake in doxorubicin\u2010resistant breast cancer cells. IUBMB Life. 2023;75(9):765\u201377.","journal-title":"IUBMB Life"},{"issue":"14","key":"5386_CR71","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1016\/j.lfs.2004.09.021","volume":"76","author":"P-C Liao","year":"2005","unstructured":"Liao P-C, Lieu C-H. Cell cycle specific induction of apoptosis and necrosis by paclitaxel in the leukemic U937 cells. Life Sci. 2005;76(14):1623\u201339.","journal-title":"Life Sci"},{"key":"5386_CR72","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-021-01687-9","author":"S Das","year":"2021","unstructured":"Das S, Shukla N, Singh SS, Kushwaha S, Shrivastava R. Mechanism of interaction between autophagy and apoptosis in cancer. Apoptosis. 2021 Oct;26(9):512-33. https:\/\/doi.org\/10.1007\/s10495-021-01687-9","journal-title":"Apoptosis"},{"issue":"1","key":"5386_CR73","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2024.2321768","volume":"25","author":"Q Niu","year":"2024","unstructured":"Niu Q, Ye S, Zhao L, Qian Y, Liu F. The role of liver cancer stem cells in hepatocellular carcinoma metastasis. Cancer Biol Ther. 2024;25(1):2321768.","journal-title":"Cancer Biol Ther"},{"issue":"1","key":"5386_CR74","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41392-025-02148-4","volume":"10","author":"Y Li","year":"2025","unstructured":"Li Y, Liu F, Cai Q, Deng L, Ouyang Q, Zhang X-F, et al. Invasion and metastasis in cancer: molecular insights and therapeutic targets. Signal Transduct Target Ther. 2025;10(1):57.","journal-title":"Signal Transduct Target Ther"},{"issue":"11","key":"5386_CR75","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19113333","volume":"19","author":"JD Middleton","year":"2018","unstructured":"Middleton JD, Stover DG, Hai T. Chemotherapy-exacerbated breast cancer metastasis: a paradox explainable by dysregulated adaptive-response. Int J Mol Sci. 2018;19(11):3333.","journal-title":"Int J Mol Sci"},{"issue":"4","key":"5386_CR76","doi-asserted-by":"publisher","first-page":"e10365","DOI":"10.1371\/journal.pone.0010365","volume":"5","author":"A Bandyopadhyay","year":"2010","unstructured":"Bandyopadhyay A, Wang L, Agyin J, Tang Y, Lin S, Yeh I-T, et al. Doxorubicin in combination with a small TGF\u03b2 inhibitor: a potential novel therapy for metastatic breast cancer in mouse models. PLoS One. 2010;5(4):e10365.","journal-title":"PLoS One"},{"issue":"4","key":"5386_CR77","doi-asserted-by":"publisher","first-page":"784","DOI":"10.3390\/nu14040784","volume":"14","author":"KK Khoja","year":"2022","unstructured":"Khoja KK, Howes M-JR, Hider R, Sharp PA, Farrell IW, Latunde-Dada GO. Cytotoxicity of fenugreek sprout and seed extracts and their bioactive constituents on MCF-7 breast cancer cells. Nutrients. 2022;14(4):784.","journal-title":"Nutrients"},{"issue":"1","key":"5386_CR78","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s43046-023-00166-3","volume":"35","author":"ND Amalina","year":"2023","unstructured":"Amalina ND, Salsabila IA, Zulfin UM, Jenie RI, Meiyanto E. In vitro synergistic effect of hesperidin and doxorubicin downregulates epithelial-mesenchymal transition in highly metastatic breast cancer cells. J Egypt Natl Cancer Inst. 2023;35(1):6.","journal-title":"J Egypt Natl Cancer Inst"},{"issue":"11","key":"5386_CR79","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.3390\/genes15111460","volume":"15","author":"P \u0160tancl","year":"2024","unstructured":"\u0160tancl P, Gr\u0161kovi\u0107 P, Dr\u017eai\u0107 S, Vi\u010di\u0107 A, Karli\u0107 R, Kora\u0107 P. RNA-sequencing identification of genes supporting HepG2 as a model cell line for hepatocellular carcinoma or hepatocytes. Genes. 2024;15(11):1460.","journal-title":"Genes"},{"issue":"1","key":"5386_CR80","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s43094-025-00862-y","volume":"11","author":"HK Nivatya","year":"2025","unstructured":"Nivatya HK, Singh A, Kumar N, Sonam, Sharma L, Singh V, et al. Assessing molecular docking tools: understanding drug discovery and design. Future J Pharm Sci. 2025;11(1):111.","journal-title":"Future J Pharm Sci"},{"key":"5386_CR81","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5c01955","author":"W Lu","year":"2025","unstructured":"Lu W, Peng X, Huang Y, Zheng Z, Zhu Z, Yin X, et al. Machine learning-guided generation of novel pseudo-natural products: applications to accelerate drug discovery. Journal of Chemical Information and Modeling. 2025;65(21):11701-15. https:\/\/doi.org\/10.1021\/acs.jcim.5c01955","journal-title":"Journal of Chemical Information and Modeling"},{"issue":"5","key":"5386_CR82","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1007\/s40242-017-7136-4","volume":"33","author":"J Wang","year":"2017","unstructured":"Wang J, Jiang W, Liu Z, Wang J, Fu T, Wang Y. Analysis and identification of chemical constituents of fenugreek by UPLC-IT-MS n and UPLC-Q-TOF-MS. Chem Res Chin Univ. 2017;33(5):721\u201330.","journal-title":"Chem Res Chin Univ"},{"issue":"4","key":"5386_CR83","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1111\/1750-3841.16970","volume":"89","author":"MH Alu'datt","year":"2024","unstructured":"Alu\u2019datt MH, Rababah T, Al-ali S, Tranchant CC, Gammoh S, Alrosan M, et al. Current perspectives on fenugreek bioactive compounds and their potential impact on human health: a review of recent insights into functional foods and other high value applications. J Food Sci. 2024;89(4):1835\u201364.","journal-title":"J Food Sci"}],"container-title":["BMC Complementary Medicine and Therapies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12906-026-05386-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12906-026-05386-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12906-026-05386-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T20:02:27Z","timestamp":1778097747000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12906-026-05386-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":83,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["5386"],"URL":"https:\/\/doi.org\/10.1186\/s12906-026-05386-3","relation":{},"ISSN":["2662-7671"],"issn-type":[{"value":"2662-7671","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,6]]},"assertion":[{"value":"1 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"171"}}