{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:28:47Z","timestamp":1785403727275,"version":"3.56.0"},"reference-count":66,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009110","name":"Natural Science Foundation of Xinjiang Uygur Autonomous Region","doi-asserted-by":"publisher","award":["2025D01C56"],"award-info":[{"award-number":["2025D01C56"]}],"id":[{"id":"10.13039\/100009110","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fifth Affiliated Hospital of Xinjiang Medical University","award":["XYDWFY-ZR-202409"],"award-info":[{"award-number":["XYDWFY-ZR-202409"]}]},{"award":["XYDWFY-ZR-202409"],"award-info":[{"award-number":["XYDWFY-ZR-202409"]}],"id":[{"id":"https:\/\/ror.org\/04f970v93","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Natural products with unique mechanisms remain of great interest because targeted cancer therapies frequently fail due to toxicity or resistance. Cardiac glycosides have demonstrated antitumor activity, but whether their effects involve microRNA regulation remains largely unexplored. This study investigates whether ouabain derived from Strophanthus gratus (Wall. &amp; Hook. ex Benth.) Baill. (SGO) exerts its antitumor effects through miR-145-5p, a known tumor suppressor, using both colorectal and breast cancer models. Methods: We performed transcriptomic profiling in HCT116 colorectal cancer cells treated with SGO, followed by in vitro assays\u2014including cell viability, caspase 3\/7 activity, flow cytometry, and colony formation\u2014in HCT116 and MCF-7 breast cancer cells. In vivo efficacy was evaluated using HCT116 xenograft models in BALB\/c-nu\/nu mice. miR-145-5p gain- and loss-of-function approaches were employed to determine its functional requirement. Results: SGO dose-dependently suppressed proliferation, induced apoptosis, and inhibited colony formation in both colorectal (HCT116) and breast (MCF-7) cancer cells, and significantly upregulated miR-145-5p levels in both cell types. Transcriptomic analysis identified miR-145-5p as a highly differentially expressed miRNA. In HCT116 xenograft models, SGO inhibited tumor growth by approximately 60% and elevated intratumoral miR-145-5p levels. Importantly, inhibition of miR-145-5p significantly attenuated these effects both in vitro and in vivo, establishing that the antitumor activity of SGO depends on the upregulation\/activation of miR-145-5p in both cancer types. Conclusions: We have found that SGO inhibits colorectal and breast cancer growth through a miR-145-5p-dependent mechanism, revealing a previously unrecognized regulatory axis for cardiac glycosides. These findings position SGO as a promising candidate for further preclinical studies and suggest that pharmacologic re-expression of miR-145-5p may represent a viable therapeutic strategy in targeted therapy.<\/jats:p>","DOI":"10.3390\/ph19071099","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"1099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["miR-145-5p Is Required for the Antitumor Activity of Strophanthus gratus-Derived Ouabain in Colorectal and Breast Cancer"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7572-2991","authenticated-orcid":false,"given":"Jianxiong","family":"Xu","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Lv","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4806-8261","authenticated-orcid":false,"given":"Zenan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Xia","sequence":"additional","affiliation":[{"name":"School of Clinica Pharmacy, Shenyang Pharmaceutical University, Shenyang 117004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0436-4277","authenticated-orcid":false,"given":"Wenfang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"},{"name":"College of Life Science and Technology, Xinjiang University, Urumqi 830017, China"},{"name":"Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","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. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","article-title":"A view on drug resistance in cancer","volume":"575","author":"Vasan","year":"2019","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41568-025-00841-8","article-title":"Advancing cancer research via comparative oncology","volume":"25","author":"Vincze","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/s41573-025-01227-z","article-title":"Metabolites as agents and targets for cancer immunotherapy","volume":"24","author":"Trefny","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41586-018-0287-8","article-title":"Targeting STING with covalent small-molecule inhibitors","volume":"559","author":"Haag","year":"2018","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143ra99","DOI":"10.1126\/scitranslmed.3003807","article-title":"Cardiac Glycosides Exert Anticancer Effects by Inducing Immunogenic Cell Death","volume":"4","author":"Menger","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1124\/mi.8.1.8","article-title":"Cardiac Glycosides as Novel Cancer Therapeutic Agents","volume":"8","author":"Newman","year":"2008","journal-title":"Mol. Interv."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ponce, A., Flores-Maldonado, C., and Contreras, R.G. (2025). Cardiac Glycosides: From Natural Defense Molecules to Emerging Therapeutic Agents. Biomolecules, 15.","DOI":"10.3390\/biom15060885"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1002\/tox.22834","article-title":"Ouabain induces apoptotic cell death in human prostate DU 145 cancer cells through DNA damage and TRAIL pathways","volume":"34","author":"Chang","year":"2019","journal-title":"Environ. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"114226","DOI":"10.1016\/j.bcp.2020.114226","article-title":"Cardiac glycosides inhibit cancer through Na\/K-ATPase-dependent cell death induction","volume":"182","author":"Geng","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ncrna.2024.11.001","article-title":"Dr. Jekyll or Mr. Hyde: The multifaceted roles of miR-145-5p in human health and disease","volume":"11","author":"Rahman","year":"2025","journal-title":"Non-Coding RNA Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/s41401-019-0290-0","article-title":"Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines","volume":"41","author":"Shen","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1007\/BF02980262","article-title":"Apoptosis-mediated cytotoxicity of ouabain, digoxin and proscillaridin A in the estrogen independent MDA-MB-231 breast cancer cells","volume":"30","author":"Winnicka","year":"2007","journal-title":"Arch. Pharmacal Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1016\/j.bbadis.2013.04.023","article-title":"Vacuolar ATPase driven potassium transport in highly metastatic breast cancer cells","volume":"1832","author":"Salyer","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Weidemann, H., Sarsour, A.D., and Brodie, C. (2025). Ouabain\u2014A double-edged sword in tumor development and progression? a review of half a century. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1685871"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5867","DOI":"10.1158\/0008-5472.CAN-05-3544","article-title":"Cardiac glycosides initiate Apo2L\/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5","volume":"66","author":"Frese","year":"2006","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Busonero, C., Leone, S., Bianchi, F., Maspero, E., Fiocchetti, M., Palumbo, O., Cipolletti, M., Bartoloni, S., and Acconcia, F. (2020). Ouabain and Digoxin Activate the Proteasome and the Degradation of the ER\u03b1 in Cells Modeling Primary and Metastatic Breast Cancer. Cancers, 12.","DOI":"10.3390\/cancers12123840"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104129","DOI":"10.1016\/j.drudis.2024.104129","article-title":"Repurposing cardiac glycosides for anticancer treatment: A review of clinical studies","volume":"29","author":"Nabil","year":"2024","journal-title":"Drug Discov. Today"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/s41576-023-00611-y","article-title":"MicroRNAs in action: Biogenesis, function and regulation","volume":"24","author":"Shang","year":"2023","journal-title":"Nat. Rev. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1007\/s00395-025-01133-w","article-title":"Calcific aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk","volume":"120","author":"Goody","year":"2025","journal-title":"Basic Res. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41580-024-00805-0","article-title":"The biogenesis and regulation of animal microRNAs","volume":"26","author":"Kim","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1158\/0008-5472.CAN-09-2021","article-title":"MicroRNA-145 Suppresses Cell Invasion and Metastasis by Directly Targeting Mucin 1","volume":"70","author":"Sachdeva","year":"2010","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wali, A.F., Ansari, A.R., Mir, P.A., El-Tanani, M., Babiker, R., Hussain, M.S., Uppal, J., Zargar, A.I., and Mir, R.H. (2025). Epigenetic Alterations in Hepatocellular Carcinoma: Mechanisms, Biomarkers, and Therapeutic Implications. Pharmaceuticals, 18.","DOI":"10.3390\/ph18091281"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s12943-017-0655-2","article-title":"Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation","volume":"16","author":"Bellissimo","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s00018-024-05505-8","article-title":"MicroRNA-145-5p inhibits the tumorigenesis of breast cancer through SENP2-regulated ubiquitination of ERK2","volume":"81","author":"Chen","year":"2024","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1164\/rccm.201901-0019LE","article-title":"Enhancing the Expression of CFTR Using Antisense Molecules against MicroRNA miR-145-5p","volume":"199","author":"Finotti","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.33165\/rmj.2022.45.3.257343","article-title":"MicroRNA Expression of Primary and Metastatic Colorectal and Breast Carcinoma","volume":"45","author":"Sricharunrat","year":"2022","journal-title":"Ramathibodi Med. J."},{"key":"ref_30","first-page":"231","article-title":"The Simultaneous Effects of miR-145-5p and hsa-let-7a-3p on Colorectal Tumorigenesis: In Vitro Evidence","volume":"14","author":"Mozammel","year":"2024","journal-title":"Adv. Pharm. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.ncrna.2024.01.016","article-title":"Inhibition of breast cancer cell growth and migration through siRNA-mediated modulation of circ_0009910\/miR-145-5p\/MUC1 axis","volume":"9","author":"Abtin","year":"2024","journal-title":"Non-Coding RNA Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Deli, H., Vakili-Ghartavol, Z., Asgari, Y., Tavoosidana, G., Eftekhar, E., and Ghahremani, M.H. (2025). The expression of exosomal and cellular miRNAs in predicting oxaliplatin resistance in colorectal cancer cells: An in silico and in vitro study. BMC Cancer, 25.","DOI":"10.1186\/s12885-024-13392-2"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, J., Chai, R., Chen, Y., Zhao, S., Bian, Y., and Wang, X. (2022). Curcumin Targeting Non-Coding RNAs in Colorectal Cancer: Therapeutic and Biomarker Implications. Biomolecules, 12.","DOI":"10.3390\/biom12101339"},{"key":"ref_34","first-page":"367","article-title":"Distinct microRNA expression pattern in breast cancer cells following anti-neoplastic treatment: A systematic review and functional analysis of microRNA target genes","volume":"44","author":"Masniza","year":"2022","journal-title":"Malays. J. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Behringer, A., Stoimenovski, D., Porsch, M., Hoffmann, K., Behre, G., Grosse, I., Kalinski, T., Haybaeck, J., and Nass, N. (2022). Relationship of micro-RNA, mRNA and eIF Expression in Tamoxifen-Adapted MCF-7 Breast Cancer Cells: Impact of miR-1972 on Gene Expression, Proliferation and Migration. Biomolecules, 12.","DOI":"10.3390\/biom12070916"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1158\/1078-0432.CCR-03-0362","article-title":"Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan","volume":"10","author":"Boyer","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1038\/sj.onc.1201445","article-title":"Resistance of MCF7 human breast carcinoma cells to TNF-induced cell death is associated with loss of p53 function","volume":"15","author":"Cai","year":"1997","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/bs.ircmb.2020.02.003","article-title":"Chapter Four\u2014Type 3 IP3 receptors: The chameleon in cancer","volume":"351","author":"Rosa","year":"2020","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Dezaire, A., Marchand, C.H., Vallet, M., Ferrand, N., Chaouch, S., Mouray, E., Larsen, A.K., Sabbah, M., Lemaire, S.D., and Prado, S. (2020). Secondary Metabolites from the Culture of the Marine-derived Fungus Paradendryphiella salina PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin. Mar. Drugs, 18.","DOI":"10.3390\/md18040191"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153780","DOI":"10.1016\/j.prp.2022.153780","article-title":"Function of miRNA-145\u20135p in the pathogenesis of human disorders","volume":"231","author":"Kadkhoda","year":"2022","journal-title":"Pathol.-Res. Pract."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1073\/pnas.0808042106","article-title":"P53 represses c-Myc through induction of the tumor suppressor miR-145","volume":"106","author":"Sachdeva","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.1038\/onc.2012.495","article-title":"Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression","volume":"32","author":"Pagliuca","year":"2012","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/sj.bjc.6605570","article-title":"miR-145 and miR-133a function as tumour suppressors and directly regulate FSCN1 expression in bladder cancer","volume":"102","author":"Chiyomaru","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/cdd.2009.117","article-title":"miR-145 participates with TP53 in a death-promoting regulatory loop and targets estrogen receptor-\u03b1 in human breast cancer cells","volume":"17","author":"Spizzo","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"161","DOI":"10.7785\/tcrt.2012.500367","article-title":"microRNA-145 Function as a Cell Growth Repressor by Directly Targeting c-Myc in Human Ovarian Cancer","volume":"13","author":"Zhang","year":"2014","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1101\/gad.1950610","article-title":"Repression of the miR-143\/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway","volume":"24","author":"Kent","year":"2010","journal-title":"Genes Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1002\/ijc.31056","article-title":"Tumor-suppressive miR-145 co-repressed by TCF4-\u03b2-catenin and PRC2 complexes forms double-negative regulation loops with its negative regulators in colorectal cancer","volume":"142","author":"Wang","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/onc.2012.28","article-title":"Loss of microRNA-143\/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop","volume":"32","author":"Zhang","year":"2012","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Clifford, R.J., and Kaplan, J.H. (2013). Human Breast Tumor Cells Are More Resistant to Cardiac Glycoside Toxicity Than Non-Tumorigenic Breast Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084306"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15606","DOI":"10.18632\/oncotarget.24581","article-title":"Selective lysis of breast carcinomas by simultaneous stimulation of sodium channels and blockade of sodium pumps","volume":"9","author":"Gould","year":"2018","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Lin, S.-C., Tsai, Y.-C., Wang, J.-L., Chin, H.-J., Tsai, C.-C., Lin, S.-C., Lin, Y.-S., Lin, B.-W., and Tsai, S.-J. (2026). Targeting NUDT21-mediated alternative polyadenylation of oncogenes ameliorates colorectal cancer malignancy and metastasis. Br. J. Cancer.","DOI":"10.1038\/s41416-026-03451-9"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s12012-020-09579-1","article-title":"Comparative Cardiotoxicity of Low Doses of Digoxin, Ouabain, and Oleandrin","volume":"20","author":"Botelho","year":"2020","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kobayashi, M., Usui-Kawanishi, F., Karasawa, T., Kimura, H., Watanabe, S., Mise, N., Kayama, F., Kasahara, T., Hasebe, N., and Takahashi, M. (2017). The cardiac glycoside ouabain activates NLRP3 inflammasomes and promotes cardiac inflammation and dysfunction. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176676"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/nrd2682","article-title":"Novel therapeutic applications of cardiac glycosides","volume":"7","author":"Prassas","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_55","first-page":"794930","article-title":"Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides","volume":"2014","author":"Orta","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbcan.2007.06.002","article-title":"Cardiotonic steroids on the road to anti-cancer therapy","volume":"1776","author":"Mijatovic","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA) -Rev. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.bbrc.2004.07.027","article-title":"Antiapoptotic effect of ouabain on human umbilical vein endothelial cells","volume":"321","author":"Trevisi","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1021\/acsmedchemlett.3c00517","article-title":"Selective (\u03b1)-l-Rhamnosylation and Neuroprotective Activity Exploration of Cardiotonic Steroids","volume":"15","author":"Rutkoski","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1248\/bpb.31.1131","article-title":"Antiproliferative Activity of Derivatives of Ouabain, Digoxin and Proscillaridin A in Human MCF-7 and MDA-MB-231 Breast Cancer Cells","volume":"31","author":"Winnicka","year":"2008","journal-title":"Biol. Pharm. Bull."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1124\/mi.3.3.157","article-title":"Na+, K+-ATPase-Mediated Signal Transduction: From Protein Interaction to Cellular Function","volume":"3","author":"Xie","year":"2003","journal-title":"Mol. Interv."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1016\/j.bbadis.2018.09.014","article-title":"Crosstalk between Na+, K+-ATPase and a volume-regulated anion channel in membrane microdomains of human cancer cells","volume":"1864","author":"Fujii","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1016\/j.biopha.2016.10.114","article-title":"Ouabain induces apoptosis and autophagy in Burkitt\u2019s lymphoma Raji cells","volume":"84","author":"Meng","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41389-023-00464-4","article-title":"The p52-ZER6\/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway","volume":"12","author":"Tang","year":"2023","journal-title":"Oncogenesis"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1038\/s41388-024-03058-5","article-title":"p52-ZER6\/IGF1R axis maintains cancer stem cell population to promote cancer progression by enhancing pro-survival mitophagy","volume":"43","author":"Li","year":"2024","journal-title":"Oncogene"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1186\/s13046-019-1376-8","article-title":"circPTN sponges miR-145-5p\/miR-330-5p to promote proliferation and stemness in glioma","volume":"38","author":"Chen","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/s41401-022-00973-9","article-title":"p52-ZER6: A determinant of tumor cell sensitivity to MDM2-p53 binding inhibitors","volume":"44","author":"Li","year":"2022","journal-title":"Acta Pharmacol. Sin."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1099\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:14:49Z","timestamp":1784279689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":66,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ph19071099"],"URL":"https:\/\/doi.org\/10.3390\/ph19071099","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}