{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:35Z","timestamp":1787028575187,"version":"build-2736575974"},"reference-count":101,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thymoquinone (TQ), the active compound in Nigella sativa (black seed), has shown promising effects against cancer in many laboratory studies. In this review, we explore how TQ works on different aspects of cancer, from stopping cancer cell growth and spread, to triggering cancer cell death, reducing inflammation, and helping the immune system fight back. We also highlight how TQ may overcome one of the biggest problems in cancer treatment\u2014chemoresistance. When used together with common treatments like chemotherapy, radiation, or immunotherapy, TQ has been shown to improve their effects and reduce harmful side effects in preclinical models. Our review further discusses how TQ affects cancer stem cells, the tumor environment, and gene regulation through epigenetics. While these findings are encouraging, the lack of human studies remains a major gap. We also address TQ\u2019s limited absorption and suggest ways to improve its delivery in the body, such as using nanoparticles or other carriers. Through this review, we aim to show the wide-ranging potential of TQ as a natural compound that may help make cancer treatments more effective and better tolerated. We call for clinical studies to take this research further and bring TQ closer to use in real-world cancer care.<\/jats:p>","DOI":"10.3390\/ijms262211029","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:49:43Z","timestamp":1763120983000},"page":"11029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Targeting Cancer Through Thymoquinone: From Molecular Mechanisms to Clinical Prospects"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1149-4208","authenticated-orcid":false,"given":"Nosayba","family":"Al-Damook","sequence":"first","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6081-1284","authenticated-orcid":false,"given":"Molham","family":"Sakkal","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6555-0642","authenticated-orcid":false,"given":"Mostafa","family":"Khair","sequence":"additional","affiliation":[{"name":"Core Technology Platforms, New York University Abu Dhabi, Abu Dhabi P.O. Box 129188, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa K.","family":"Mousa","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6036-1022","authenticated-orcid":false,"given":"Ghalia","family":"Khoder","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceuticals Technology, College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"},{"name":"Sharjah Institute for Medical Research, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2465-0812","authenticated-orcid":false,"given":"Rose","family":"Ghemrawi","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"},{"name":"AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Arafat, M., Sakkal, M., Beiram, R., and AbuRuz, S. (2024). Nanomedicines: Emerging Platforms in Smart Chemotherapy Treatment\u2014A Recent Review. Pharmaceuticals, 17.","DOI":"10.3390\/ph17030315"},{"key":"ref_2","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.69709\/CellEngC.2025.115467","article-title":"Synergistic Modulation of ER Stress and Insulin Potentiation Therapy for Enhanced Cancer Treatment","volume":"1","author":"Sakkal","year":"2025","journal-title":"Cell Eng. Connect"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11149","DOI":"10.1002\/cam4.5698","article-title":"Role of tumor microenvironment in cancer progression and therapeutic strategy","volume":"12","author":"Wang","year":"2023","journal-title":"Cancer Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ghemrawi, R., Abuamer, L., Kremesh, S., Hussien, G., Ahmed, R., Mousa, W., Khoder, G., and Khair, M. (2024). Revolutionizing Cancer Treatment: Recent Advances in Immunotherapy. Biomedicines, 12.","DOI":"10.3390\/biomedicines12092158"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Asma, S.T., Acaroz, U., Imre, K., Morar, A., Shah, S.R.A., Hussain, S.Z., Arslan-Acaroz, D., Demirbas, H., Hajrulai-Musliu, Z., and Istanbullugil, F.R. (2022). Natural Products\/Bioactive Compounds as a Source of Anticancer Drugs. Cancers, 14.","DOI":"10.3390\/cancers14246203"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100020","DOI":"10.1016\/j.prmcm.2021.100020","article-title":"Thymoquinone and its pharmacological perspective: A review","volume":"1","author":"Tabassum","year":"2021","journal-title":"Pharmacol. Res.-Mod. Chin. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zeinali, N., Mahmoudzadeh, V., Anarjani, A., Ebrahimnejad, M., Yousefi, B., and Valizadeh, A. (2024). Thymoquinone Increases the Sensitivity of SW-480 Colon Cancer Cells to 5-Fluorouracil. BioMed Res. Int., 2024.","DOI":"10.1155\/2024\/6231095"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"112604","DOI":"10.1016\/j.fct.2021.112604","article-title":"Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2\/STAT3 signaling pathway in human melanoma cells","volume":"157","author":"Raut","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s13596-024-00785-8","article-title":"Anticancer activity of thymoquinone and its combinations with doxorubicin and linseed oil in the treatment of xenograft tumors","volume":"25","author":"Shadyro","year":"2025","journal-title":"Adv. Tradit. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"363","DOI":"10.21873\/cgp.20507","article-title":"The Role of ER Stress and the Unfolded Protein Response in Cancer","volume":"22","author":"Ghemrawi","year":"2025","journal-title":"Cancer Genom. Proteom."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liang, D., Khoonkari, M., Avril, T., Chevet, E., and Kruyt, F.A.E. (2021). The unfolded protein response as regulator of cancer stemness and differentiation: Mechanisms and implications for cancer therapy. Biochem. Pharmacol., 192.","DOI":"10.1016\/j.bcp.2021.114737"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"522","DOI":"10.5306\/wjco.v12.i7.522","article-title":"Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells","volume":"12","author":"Fatfat","year":"2021","journal-title":"World J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Adinew, G.M., Taka, E., Mochona, B., Badisa, R.B., Mazzio, E.A., Elhag, R., and Soliman, K.F.A. (2021). Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment. Nutrients, 14.","DOI":"10.3390\/nu14010079"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1038\/s12276-023-01020-1","article-title":"Metabolic reprogramming and epigenetic modifications in cancer: From the impacts and mechanisms to the treatment potential","volume":"55","author":"Xu","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.2174\/1386207323999201027225305","article-title":"Molecular Mechanisms of Thymoquinone as Anticancer Agent","volume":"24","author":"Alhmied","year":"2021","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Majdalawieh, A.F., Al-Samaraie, S., and Terro, T.M. (2024). Molecular Mechanisms and Signaling Pathways Underlying the Therapeutic Potential of Thymoquinone Against Colorectal Cancer. Molecules, 29.","DOI":"10.3390\/molecules29245907"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4103\/2008-7802.180412","article-title":"Effect of thymoquinone on P53 gene expression and consequence apoptosis in breast cancer cell line","volume":"7","author":"Dastjerdi","year":"2016","journal-title":"Int. J. Prev. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"821","DOI":"10.3892\/or.2014.3223","article-title":"Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src-mediated phosphorylation of EGF receptor tyrosine kinase","volume":"32","author":"Kundu","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/1407840","article-title":"Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation","volume":"2016","author":"Relles","year":"2016","journal-title":"Adv. Prev. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1258\/ebm.2010.009369","article-title":"Studies on molecular mechanisms of growth inhibitory effects of thymoquinone against prostate cancer cells: Role of reactive oxygen species","volume":"235","author":"Koka","year":"2010","journal-title":"Exp. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"160","DOI":"10.4161\/cbt.6.2.3575","article-title":"Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells","volume":"6","author":"Roepke","year":"2007","journal-title":"Cancer Biol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3892\/or.2012.2165","article-title":"Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-\u03baB pathway","volume":"29","author":"Peng","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gurung, R.L., Lim, S.N., Khaw, A.K., Soon, J.F.F., Shenoy, K., Mohamed Ali, S., Jayapal, M., Sethu, S., Baskar, R., and Hande, M.P. (2010). Thymoquinone Induces Telomere Shortening, DNA Damage and Apoptosis in Human Glioblastoma Cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012124"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11010-013-1772-x","article-title":"Pronounced transcriptional regulation of apoptotic and TNF\u2013NF-kappa-B signaling genes during the course of thymoquinone mediated apoptosis in HeLa cells","volume":"383","author":"Sakalar","year":"2013","journal-title":"Mol. Cell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s13277-014-2628-z","article-title":"Thymoquinone inhibits proliferation and invasion of human nonsmall-cell lung cancer cells via ERK pathway","volume":"36","author":"Yang","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s11010-013-1930-1","article-title":"Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis","volume":"389","author":"Ashour","year":"2014","journal-title":"Mol. Cell. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Homayoonfal, M., Asemi, Z., and Yousefi, B. (2022). Potential anticancer properties and mechanisms of thymoquinone in osteosarcoma and bone metastasis. Cell. Mol. Biol. Lett., 27.","DOI":"10.1186\/s11658-022-00320-0"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7782","DOI":"10.1158\/0008-5472.CAN-07-1483","article-title":"Androgen Receptor\u2013 and E2F-1\u2013Targeted Thymoquinone Therapy for Hormone-Refractory Prostate Cancer","volume":"67","author":"Kaseb","year":"2007","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"879","DOI":"10.31557\/APJCP.2021.22.3.879","article-title":"Thymoquinone Suppresses Cell Proliferation and Enhances Apoptosis of HL60 Leukemia Cells through Re-Expression of JAK\/STAT Negative Regulators","volume":"22","author":"Almajali","year":"2021","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_31","first-page":"107","article-title":"In vitro inhibition of growth and induction of apoptosis in cancer cell lines by thymoquinone","volume":"22","author":"Shoieb","year":"2003","journal-title":"Int. J. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1080\/01635581.2013.878739","article-title":"Thymoquinone, A Bioactive Component of Black Caraway Seeds, Causes G1 Phase Cell Cycle Arrest and Apoptosis in Triple-Negative Breast Cancer Cells with Mutant p53","volume":"66","author":"Sutton","year":"2014","journal-title":"Nutr. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/j.1476-5381.2010.00874.x","article-title":"Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway","volume":"161","author":"Li","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19580","DOI":"10.18632\/oncotarget.3973","article-title":"Thymoquinone inhibits cancer metastasis by downregulating TWIST1 expression to reduce epithelial to mesenchymal transition","volume":"6","author":"Khan","year":"2015","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Shanmugam, M.K., Ahn, K.S., Hsu, A., Woo, C.C., Yuan, Y., Tan, K.H.B., Chinnathambi, A., Alahmadi, T.A., Alharbi, S.A., and Koh, A.P.F. (2018). Thymoquinone Inhibits Bone Metastasis of Breast Cancer Cells Through Abrogation of the CXCR4 Signaling Axis. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01294"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"686","DOI":"10.7150\/ijms.32763","article-title":"Thymoquinone inhibits metastasis of renal cell carcinoma cell 786-O-SI3 associating with downregulation of MMP-2 and u-PA and suppression of PI3K\/Src signaling","volume":"16","author":"Liou","year":"2019","journal-title":"Int. J. Med. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1111\/cas.13808","article-title":"Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK\/mTOR signaling pathway","volume":"109","author":"Zhang","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Al-Hayali, M., Garces, A., Stocks, M., Collins, H., and Bradshaw, T.D. (2021). Concurrent Reactive Oxygen Species Generation and Aneuploidy Induction Contribute to Thymoquinone Anticancer Activity. Molecules, 26.","DOI":"10.3390\/molecules26175136"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s10495-009-0421-z","article-title":"Reactive oxygen species mediate thymoquinone-induced apoptosis and activate ERK and JNK signaling","volume":"15","author":"Chatila","year":"2010","journal-title":"Apoptosis"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5308","DOI":"10.1158\/1078-0432.CCR-07-5023","article-title":"The Double-Edged Sword of Autophagy Modulation in Cancer","volume":"15","author":"White","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chu, S.C., Hsieh, Y.S., Yu, C.C., Lai, Y.Y., and Chen, P.N. (2014). Thymoquinone Induces Cell Death in Human Squamous Carcinoma Cells via Caspase Activation-Dependent Apoptosis and LC3-II Activation-Dependent Autophagy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101579"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1021\/jf5054063","article-title":"Thymoquinone Induces Caspase-Independent, Autophagic Cell Death in CPT-11-Resistant LoVo Colon Cancer via Mitochondrial Dysfunction and Activation of JNK and p38","volume":"63","author":"Chen","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Racoma, I.O., Meisen, W.H., Wang, Q.E., Kaur, B., and Wani, A.A. (2013). Thymoquinone Inhibits Autophagy and Induces Cathepsin-Mediated, Caspase-Independent Cell Death in Glioblastoma Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072882"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cbi.2018.06.013","article-title":"Thymoquinone induces apoptosis in bladder cancer cell via endoplasmic reticulum stress-dependent mitochondrial pathway","volume":"292","author":"Zhang","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Al Bitar, S., Ballout, F., Monzer, A., Kanso, M., Saheb, N., Mukherji, D., Faraj, W., Tawil, A., Doughan, S., and Hussein, M. (2022). Thymoquinone Radiosensitizes Human Colorectal Cancer Cells in 2D and 3D Culture Models. Cancers, 14, Erratum in Cancers\u00a02025, 17, 2449.","DOI":"10.3390\/cancers17152449"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lee, Y.M., Kim, G.H., Park, E.J., Oh, T.I., Lee, S., Kan, S.Y., Kang, H., Kim, B.M., Kim, J.H., and Lim, J.-H. (2019). Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1\u03b1-Mediated Glycolysis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051092"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1007\/s10620-014-3394-x","article-title":"Thymoquinone Pretreatment Overcomes the Insensitivity and Potentiates the Antitumor Effect of Gemcitabine Through Abrogation of Notch1, PI3K\/Akt\/mTOR Regulated Signaling Pathways in Pancreatic Cancer","volume":"60","author":"Mu","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s12032-024-02586-0","article-title":"GRP78 as a potential therapeutic target in cancer treatment: An updated review of its role in chemoradiotherapy resistance of cancer cells","volume":"42","author":"Lin","year":"2025","journal-title":"Med. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"102786","DOI":"10.1016\/j.tice.2025.102786","article-title":"The significance of the activating transcription factor 6 gene in the pathogenesis of drug resistant cancer","volume":"93","author":"Khanishayan","year":"2025","journal-title":"Tissue Cell"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Wang, P., Han, L., Yu, M., Cao, Z., Li, X., Shao, Y., and Zhu, G. (2021). The Prognostic Value of PERK in Cancer and Its Relationship With Immune Cell Infiltration. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.648752"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.ccell.2022.08.016","article-title":"Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses","volume":"40","author":"Mandula","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1080\/01635581.2020.1751216","article-title":"Antiproliferative Effects of Thymoquinone in MCF-7 Breast and HepG2 Liver Cancer Cells: Possible Role of Ceramide and ER Stress","volume":"73","author":"Aslan","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Landucci, E., Mazzantini, C., Buonvicino, D., Pellegrini-Giampietro, D.E., and Bergonzi, M.C. (2021). Neuroprotective Effects of Thymoquinone by the Modulation of ER Stress and Apoptotic Pathway in In Vitro Model of Excitotoxicity. Molecules, 26.","DOI":"10.3390\/molecules26061592"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.biopha.2017.08.018","article-title":"Thymoquinone prevents endoplasmic reticulum stress and mitochondria-induced apoptosis in a rat model of partial hepatic warm ischemia reperfusion","volume":"94","author":"Bouhlel","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"634","DOI":"10.18632\/oncotarget.1596","article-title":"Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-\u03baB regulated gene products in multiple myeloma xenograft mouse model","volume":"5","author":"Siveen","year":"2014","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/sj.bjc.6605762","article-title":"Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer","volume":"103","author":"Lugli","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/5416923","article-title":"Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment","volume":"2018","author":"Phi","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1186\/s12943-022-01682-x","article-title":"Tumor microenvironment enriches the stemness features: The architectural event of therapy resistance and metastasis","volume":"21","author":"Nallasamy","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e265","DOI":"10.1002\/mco2.265","article-title":"Understanding and targeting resistance mechanisms in cancer","volume":"4","author":"Lei","year":"2023","journal-title":"MedComm"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"155","DOI":"10.5530\/phrev.2020.14.19","article-title":"Thymoquinone: A Potential Therapy against Cancer Stem Cells","volume":"14","author":"Ballout","year":"2020","journal-title":"Pharmacogn. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41419-019-1611-4","article-title":"Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells","volume":"10","author":"Ndreshkjana","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Bashmail, H.A., Alamoudi, A.A., Noorwali, A., Hegazy, G.A., AJabnoor, G., Choudhry, H., and Al-Abd, A.M. (2018). Thymoquinone synergizes gemcitabine anti-breast cancer activity via modulating its apoptotic and autophagic activities. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-30046-z"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Ibiyeye, K.M., and Zuki, A.B.Z. (2020). Cockle Shell-Derived Aragonite CaCO3 Nanoparticles for Co-Delivery of Doxorubicin and Thymoquinone Eliminates Cancer Stem Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051900"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Jehan, S., Zhong, C., Li, G., Zulqarnain Bakhtiar, S., Li, D., and Sui, G. (2020). Thymoquinone Selectively Induces Hepatocellular Carcinoma Cell Apoptosis in Synergism with Clinical Therapeutics and Dependence of p53 Status. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.555283"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Raskov, H., Orhan, A., Gaggar, S., and G\u00f6genur, I. (2021). Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.668731"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Wu, M.H., Lee, W.J., Hua, K.T., Kuo, M.L., and Lin, M.T. (2015). Macrophage Infiltration Induces Gastric Cancer Invasiveness by Activating the \u03b2-Catenin Pathway. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134122"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"136","DOI":"10.15430\/JCP.2020.25.3.136","article-title":"Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets","volume":"25","author":"Gomathinayagam","year":"2020","journal-title":"J. Cancer Prev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.bionut.2012.03.011","article-title":"Anti-angiogenic activity of thymoquinone by the down-regulation of VEGF using zebrafish (Danio rerio) model","volume":"2","author":"Paramasivam","year":"2012","journal-title":"Biomed. Prev. Nutr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/S1567-5769(02)00139-X","article-title":"Thymoquinone suppresses expression of inducible nitric oxide synthase in rat macrophages","volume":"2","author":"Matsuyama","year":"2002","journal-title":"Int. Immunopharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s12943-015-0463-5","article-title":"Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer","volume":"14","author":"Wilson","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"8482","DOI":"10.1111\/jcmm.14738","article-title":"Thymoquinone suppresses platelet-derived growth factor-BB\u2013induced vascular smooth muscle cell proliferation, migration and neointimal formation","volume":"23","author":"Zhu","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e159839","DOI":"10.1172\/JCI159839","article-title":"Hypoxia-inducible factors: Cancer progression and clinical translation","volume":"132","author":"Wicks","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1042\/BCJ20210084","article-title":"The roles of epigenetics in cancer progression and metastasis","volume":"478","author":"Chen","year":"2021","journal-title":"Biochem. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA Methylation and Its Basic Function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-981-15-8104-5_1","article-title":"Overview of Histone Modification","volume":"1283","author":"Zhang","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/carcin\/bgp220","article-title":"Epigenetics in cancer","volume":"31","author":"Sharma","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.mrfmmm.2010.10.007","article-title":"Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells","volume":"706","author":"Arafa","year":"2011","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1039\/C5MB00412H","article-title":"Insights into the molecular interactions of thymoquinone with histone deacetylase: Evaluation of the therapeutic intervention potential against breast cancer","volume":"12","author":"Parbin","year":"2016","journal-title":"Mol. Biosyst."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4394","DOI":"10.1158\/0008-5472.CAN-12-0429","article-title":"AMPK Promotes p53 Acetylation via Phosphorylation and Inactivation of SIRT1 in Liver Cancer Cells","volume":"72","author":"Lee","year":"2012","journal-title":"Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1177\/1535370214557218","article-title":"SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells","volume":"240","author":"Zhang","year":"2015","journal-title":"Exp. Biol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"34453","DOI":"10.18632\/oncotarget.16431","article-title":"Thymoquinone exerts potent growth-suppressive activity on leukemia through DNA hypermethylation reversal in leukemia cells","volume":"8","author":"Pang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1007\/s13277-013-1002-x","article-title":"Twist: A molecular target in cancer therapeutics","volume":"34","author":"Khan","year":"2013","journal-title":"Tumor Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"21362","DOI":"10.18632\/oncotarget.15214","article-title":"MicroRNA-34a targets epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs) and inhibits breast cancer cell migration and invasion","volume":"8","author":"Imani","year":"2017","journal-title":"Oncotarget"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1080\/10520295.2018.1437472","article-title":"Effects of thymoquinone on liver miRNAs and oxidative stress in Ehrlich acid mouse solid tumor model","volume":"93","author":"Meral","year":"2018","journal-title":"Biotech. Histochem."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Mostofa, A.G.M., Hossain, M.K., Basak, D., and Bin Sayeed, M.S. (2017). Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00295"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Zhao, Z., Liu, L., Chen, H., Li, S., Guo, Y., Hou, X., and Yang, J. (2023). Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1\u03b1. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1138265"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s00280-010-1386-x","article-title":"Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin","volume":"67","author":"Schobert","year":"2011","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s12094-014-1206-6","article-title":"Novel combination of docetaxel and thymoquinone induces synergistic cytotoxicity and apoptosis in DU-145 human prostate cancer cells by modulating PI3K\u2013AKT pathway","volume":"17","author":"Dirican","year":"2015","journal-title":"Clin. Transl. Oncol."},{"key":"ref_89","first-page":"245","article-title":"Thymoquinone Could Increase The Efficacy of Tamoxifen Induced Apoptosis in Human Breast Cancer Cells: An In Vitro Study","volume":"18","author":"Khazaei","year":"2016","journal-title":"Cell J."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Bashmail, H.A., Alamoudi, A.A., Noorwali, A., Hegazy, G.A., Ajabnoor, G.M., and Al-Abd, A.M. (2020). Thymoquinone Enhances Paclitaxel Anti-Breast Cancer Activity via Inhibiting Tumor-Associated Stem Cells Despite Apparent Mathematical Antagonism. Molecules, 25.","DOI":"10.3390\/molecules25020426"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.2217\/nnm-2021-0103","article-title":"Thymoquinone and its Nanoformulation Attenuate Colorectal and Breast Cancers and Alleviate Doxorubicin-Induced Cardiotoxicity","volume":"16","author":"Salaheldin","year":"2021","journal-title":"Nanomedicine"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1016\/j.clml.2014.04.014","article-title":"Antiproliferative and Proapoptotic Effects of Topotecan in Combination with Thymoquinone on Acute Myelogenous Leukemia","volume":"14","author":"Khalife","year":"2014","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1042\/CBI20100701","article-title":"Radiosensitization in human breast carcinoma cells by thymoquinone: Role of cell cycle and apoptosis","volume":"35","author":"Kumar","year":"2011","journal-title":"Cell Biol. Int."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9018","DOI":"10.3390\/curroncol29110707","article-title":"Thymoquinone Plus Immunotherapy in Extra-Pulmonary Neuroendocrine Carcinoma: Case Series for a Novel Combination","volume":"29","author":"Mohamed","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7703","DOI":"10.2147\/IJN.S262395","article-title":"Pharmacokinetics and Biodistribution of Thymoquinone-loaded Nanostructured Lipid Carrier After Oral and Intravenous Administration into Rats","volume":"15","author":"Latifah","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.31557\/APJCP.2019.20.4.1153","article-title":"Thymoquinone Augments Cyclophosphamide-Mediated Inhibition of Cell Proliferation in Breast Cancer Cells","volume":"20","author":"Khan","year":"2019","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.2174\/1871520621666210624111613","article-title":"Synergistic Role of Thymoquinone on Anticancer Activity of 5-Fluorouracil in Triple Negative Breast Cancer Cells","volume":"22","author":"Zheng","year":"2022","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Rajput, S., Kumar, B.P., Sarkar, S., Das, S., Azab, B., Santhekadur, P.K., Das, S.K., Emdad, L., Sarkar, D., and Fisher, P.B. (2013). Targeted Apoptotic Effects of Thymoquinone and Tamoxifen on XIAP Mediated Akt Regulation in Breast Cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061342"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1007\/s13277-015-4307-0","article-title":"The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer","volume":"37","author":"Sezen","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_100","first-page":"391","article-title":"The effects of thymoquinone and Doxorubicin on leukemia and cardiomyocyte cell lines","volume":"50","author":"Brown","year":"2014","journal-title":"Biomed. Sci. Instrum."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Atteia, H.H., Arafa, M.H., Mohammad, N.S., Amin, D.M., and Sakr, A.T. (2021). Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma. J. Biochem. Mol. Toxicol., 35.","DOI":"10.1002\/jbt.22924"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:51:56Z","timestamp":1763121116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":101,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211029"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211029","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,14]]}}}