{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:41Z","timestamp":1790773301506,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":29,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioFactors"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Hepatocellular carcinoma (HCC) remains a major challenge threatening global health. It has a high incidence with poor prognosis, and its response to current conventional therapies is not satisfactory, so we need to explore new effective therapies to address this problem. Targeted therapy represents a promising approach, but the therapeutic efficacy of targeting ion transporters and nuclear transport proteins, such as Na+\/K+\/2Cl\u2212 cotransporter 1 (NKCC1) and Karyopherin \u03b21 (KPN\u03b21), remains poorly investigated. This study aims to assess the therapeutic efficacy of targeting NKCC1 and KPN\u03b21 individually and in combination. We also explored the roles of these transporters in tumor cell proliferation and HCC progression. To achieve this aim, an HCC rat model was used, induced by diethylnitrosamine and phenobarbital. The evaluation included histopathological examination and assessment of liver function biomarkers (alanine aminotransferase and aspartate aminotransferase), cell cycle regulators (Cyclin D1, p21, E2F1), proliferation (Ki\u201067), apoptosis (Caspase\u20103), and expression of NKCC1 and KPN\u03b21. This study revealed that NKCC1 and KPN\u03b21 were upregulated in the HCC group. This increase was associated with increased proliferation and suppressed apoptosis. Targeting these proteins, particularly in combination, significantly improved liver function. It also induced cell cycle arrest, reduced proliferative markers, and enhanced apoptosis. These findings indicate that NKCC1 and KPN\u03b21 could serve as possible therapeutic targets in HCC treatment.<\/jats:p>","DOI":"10.1002\/biof.70155","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:49:09Z","timestamp":1790772549000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>KPN\u03b21<\/scp>\n                    and\n                    <scp>NKCC1<\/scp>\n                    Modulators as Key Players in\n                    <scp>HCC<\/scp>\n                    : Possible Interventions in Cell Cycle Arrest and Apoptosis"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0695-2251","authenticated-orcid":false,"given":"Shimaa A.","family":"Abass","sequence":"first","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy Kafrelsheikh University  Kafrelsheikh Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7466-7318","authenticated-orcid":false,"given":"Doaa H.","family":"Elhasanein","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy Kafrelsheikh University  Kafrelsheikh Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramadan A.","family":"Eldomany","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy Kafrelsheikh University  Kafrelsheikh Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherin","family":"Zakaria","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Kafrelsheikh University  Kafrelsheikh Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"e_1_2_11_2_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 H.","year":"2021","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global Burden of Primary Liver Cancer in 2020 and Predictions to 2040","volume":"77","author":"Rumgay H.","year":"2022","journal-title":"Journal of Hepatology"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3390\/diseases13070207","article-title":"Hepatocellular Carcinoma: A Comprehensive Review","volume":"13","author":"Amin N.","year":"2025","journal-title":"Diseases"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"4028","DOI":"10.3390\/cancers14164028","article-title":"Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities","volume":"14","author":"Laface C.","year":"2022","journal-title":"Cancers"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s12032-015-0559-1","article-title":"Suppression of the Nuclear Transporter\u2010KPN\u03b21 Expression Inhibits Tumor Proliferation in Hepatocellular Carcinoma","volume":"32","author":"Yang L.","year":"2015","journal-title":"Medical Oncology"},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1007\/s13402-022-00709-1","article-title":"DNASE1L3 Inhibits Hepatocellular Carcinoma by Delaying Cell Cycle Progression Through CDK2","volume":"45","author":"Sun J.","year":"2022","journal-title":"Cellular Oncology"},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/S0092-8674(00)81666-9","article-title":"Transport of Proteins and RNAs in and Out of the Nucleus","volume":"99","author":"Nakielny S.","year":"1999","journal-title":"Cell"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"10455","DOI":"10.2147\/OTT.S210048","article-title":"Inhibition of KPNB1 Inhibits Proliferation and Promotes Apoptosis of Chronic Myeloid Leukemia Cells Through Regulation of E2F1","volume":"12","author":"Wang T.","year":"2019","journal-title":"Oncotargets and Therapy"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.7150\/jca.49709","article-title":"NKCC1 Promotes Proliferation, Invasion and Migration in Human Gastric Cancer Cells via Activation of the MAPK\u2010JNK\/EMT Signaling Pathway","volume":"12","author":"Wang J.\u2010f.","year":"2021","journal-title":"Journal of Cancer"},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"6844","DOI":"10.3748\/wjg.v20.i22.6844","article-title":"Role of the Na+\/K+\/2Cl\u2010Cotransporter NKCC1 in Cell Cycle Progression in Human Esophageal Squamous Cell Carcinoma","volume":"20","author":"Shiozaki A.","year":"2014","journal-title":"World Journal of Gastroenterology"},{"key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"66328","DOI":"10.18632\/oncotarget.20240","article-title":"Discovery of NKCC1 as a Potential Therapeutic Target to Inhibit Hepatocellular Carcinoma Cell Growth and Metastasis","volume":"8","author":"Zhou Y.","year":"2017","journal-title":"Oncotarget"},{"key":"e_1_2_11_13_1","first-page":"E7301","article-title":"In Vivo Loss\u2010Of\u2010Function Screens Identify KPNB1 as a New Druggable Oncogene in Epithelial Ovarian Cancer","volume":"114","author":"Kodama M.","year":"2017","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.2170\/physiolsci.RP010806","article-title":"Furosemide, a Blocker of Na+\/K+\/2Cl\u2212 Cotransporter, Diminishes Proliferation of Poorly Differentiated Human Gastric Cancer Cells by Affecting G0\/G1 State","volume":"56","author":"Shiozaki A.","year":"2006","journal-title":"Journal of Physiological Sciences"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3164\/jcbn.16-122","article-title":"Effectiveness of Tolvaptan Monotherapy and Low\u2010Dose Furosemide\/Tolvaptan Combination Therapy for Hepatoprotection and Diuresis in a Rat Cirrhotic Model","volume":"61","author":"Tanabe N.","year":"2017","journal-title":"Journal of Clinical Biochemistry and Nutrition"},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41523-021-00229-5","article-title":"Ivermectin Converts Cold Tumors Hot and Synergizes With Immune Checkpoint Blockade for Treatment of Breast Cancer","volume":"7","author":"Draganov D.","year":"2021","journal-title":"npj Breast Cancer"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A Simple Practice Guide for Dose Conversion Between Animals and Human","volume":"7","author":"Nair A. B.","year":"2016","journal-title":"Journal of Basic and Clinical Pharmacy"},{"key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/hep.24433","article-title":"Saffron: A Potential Candidate for a Novel Anticancer Drug Against Hepatocellular Carcinoma","volume":"54","author":"Amin A.","year":"2011","journal-title":"Hepatology"},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.3390\/cancers15164063","article-title":"Combining Crocin and Sorafenib Improves Their Tumor\u2010Inhibiting Effects in a Rat Model of Diethylnitrosamine\u2010Induced Cirrhotic\u2010Hepatocellular Carcinoma","volume":"15","author":"Awad B.","year":"2023","journal-title":"Cancers"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"148251","DOI":"10.1016\/j.brainres.2023.148251","article-title":"Basic Physiological Effects of Ketamine\u2010Xylazine Mixture as a General Anesthetic Preparation for Rodent Surgeries","volume":"1804","author":"Irwin M. R.","year":"2023","journal-title":"Brain Research"},{"key":"e_1_2_11_21_1","volume-title":"Theory and Practice of Histological Techniques","author":"Bancroft J. D.","year":"2008"},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1093\/ajcp\/28.1.56","article-title":"A Colorimetric Method for the Determination of Serum Glutamic Oxalacetic and Glutamic Pyruvic Transaminases","volume":"28","author":"Reitman S.","year":"1957","journal-title":"American Journal of Clinical Pathology"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","first-page":"120369","DOI":"10.1016\/j.lfs.2022.120369","article-title":"Dual Regulating of Mitochondrial Fusion and Timp\u20103 by Leflunomide and Diallyl Disulfide Combination Suppresses Diethylnitrosamine\u2010Induced Hepatocellular Tumorigenesis in Rats","volume":"294","author":"Abdel\u2010Hamid N. M.","year":"2022","journal-title":"Life Sciences"},{"key":"e_1_2_11_24_1","unstructured":"E.Cahyani A.Putra andP.Subchan \u201cPotential Use of the Gel Extract of Butterfly Pea Flower as Topical Therapy to Prevent Photodamage by Downregulating TNF\u2010\u03b1 and Caspase\u20103 Expression Levels in UVB\u2010Exposed Rats \u201d2023."},{"key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s12993-015-0064-x","article-title":"The Protective Effect of Caffeic Acid on Global Cerebral Ischemia\u2010Reperfusion Injury in Rats","volume":"11","author":"Liang G.","year":"2015","journal-title":"Behavioral and Brain Functions"},{"key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/s41419-020-03030-7","article-title":"AFP Promotes HCC Progression by Suppressing the HuR\u2010Mediated Fas\/FADD Apoptotic Pathway","volume":"11","author":"Chen T.","year":"2020","journal-title":"Cell Death & Disease"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.1038\/s41388-021-01881-8","article-title":"PARP14 Regulates Cyclin D1 Expression to Promote Cell\u2010Cycle Progression","volume":"40","author":"O'Connor M. J.","year":"2021","journal-title":"Oncogene"},{"key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41420-025-02416-w","article-title":"Dual Role of p21 in Regulating Apoptosis and Mitotic Integrity in Response to Doxorubicin in Colon Cancer Cells","volume":"11","author":"Kim H.","year":"2025","journal-title":"Cell Death Discovery"},{"key":"e_1_2_11_29_1","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1080\/15384101.2017.1338221","article-title":"Inhibition of E2F1 Activity and Cell Cycle Progression by Arsenic via Retinoblastoma Protein","volume":"16","author":"Sheldon L. A.","year":"2017","journal-title":"Cell Cycle"},{"key":"e_1_2_11_30_1","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.21608\/mjcu.2019.53903","article-title":"Association of ki\u201067 Expression and the Aggressiveness of Hepatocellular Carcinoma","volume":"87","author":"Nanis S. H.","year":"2019","journal-title":"Medical Journal of Cairo University"},{"key":"e_1_2_11_31_1","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1007\/s12010-022-04203-0","article-title":"Simvastatin Induces Apoptosis and Suppresses Hepatocellular Carcinoma Induced in Rats","volume":"195","author":"Elleithi Y. A.","year":"2023","journal-title":"Applied Biochemistry and Biotechnology"},{"issue":"11","key":"e_1_2_11_32_1","doi-asserted-by":"crossref","first-page":"16131","DOI":"10.1007\/s00210-025-04098-8","article-title":"Therapeutic Efficacy of Canagliflozin Against Hepatocarcinogenesis Induced by CDD\/DEN\/TAA in a Rat Model: Regulation of AMPK\/HIF\u20101\u03b1\/YAP\u20101\/TAZ Signaling Pathways","volume":"398","author":"Fayed H. M.","year":"2025","journal-title":"Naunyn\u2010Schmiedeberg's Archives of Pharmacology"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12935-024-03629-2","article-title":"Predicting Hepatocellular Carcinoma Outcomes and Immune Therapy Response With ATP\u2010Dependent Chromatin Remodeling\u2010Related Genes, Highlighting MORF4L1 as a Promising Target","volume":"25","author":"Xu C.","year":"2025","journal-title":"Cancer Cell International"},{"key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"4700","DOI":"10.1038\/s41388-019-0745-2","article-title":"Inhibition of Karyopherin Beta 1 Suppresses Prostate Cancer Growth","volume":"38","author":"Yang J.","year":"2019","journal-title":"Oncogene"},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"819688","DOI":"10.3389\/fonc.2022.819688","article-title":"Comprehensive Analysis of the Oncogenic, Genomic Alteration, and Immunological Landscape of Cation\u2010Chloride Cotransporters in Pan\u2010Cancer","volume":"12","author":"Wang J.","year":"2022","journal-title":"Frontiers in Oncology"},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","first-page":"175925","DOI":"10.1016\/j.ejphar.2023.175925","article-title":"KPNB1\u2010Mediated Nuclear Import in Cancer","volume":"955","author":"Shi Q.","year":"2023","journal-title":"European Journal of Pharmacology"},{"key":"e_1_2_11_37_1","doi-asserted-by":"crossref","first-page":"176697","DOI":"10.1016\/j.ejphar.2024.176697","article-title":"Targeting KPNB1 With Genkwadaphnin Suppresses Gastric Cancer Progression Through the Nur77\u2010Mediated Signaling Pathway","volume":"977","author":"Zhang C.","year":"2024","journal-title":"European Journal of Pharmacology"},{"key":"e_1_2_11_38_1","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.1111\/liv.14223","article-title":"Biology and Significance of Alpha\u2010Fetoprotein in Hepatocellular Carcinoma","volume":"39","author":"Galle P. R.","year":"2019","journal-title":"Liver International"},{"key":"e_1_2_11_39_1","doi-asserted-by":"crossref","first-page":"eadc8911","DOI":"10.1126\/sciadv.adc8911","article-title":"ACTR5 Controls CDKN2A and Tumor Progression in an INO80\u2010Independent Manner","volume":"8","author":"Xu X.","year":"2022","journal-title":"Science Advances"},{"key":"e_1_2_11_40_1","doi-asserted-by":"crossref","first-page":"285","DOI":"10.2147\/DDDT.S237393","article-title":"Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin","volume":"14","author":"Liu J.","year":"2020","journal-title":"Drug Design, Development and Therapy"},{"key":"e_1_2_11_41_1","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.7150\/ijms.76623","article-title":"Ivermectin Induces Cell Cycle Arrest and Caspase\u2010Dependent Apoptosis in Human Urothelial Carcinoma Cells","volume":"19","author":"Tung C.\u2010L.","year":"2022","journal-title":"International Journal of Medical Sciences"},{"key":"e_1_2_11_42_1","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1089\/cbr.2020.4342","article-title":"Clinical Implication of E2F Transcription Factor 1 in Hepatocellular Carcinoma Tissues","volume":"38","author":"Ye W.\u2010Y.","year":"2023","journal-title":"Cancer Biotherapy & Radiopharmaceuticals"},{"key":"e_1_2_11_43_1","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/s41419-022-05182-0","article-title":"Integrated Analysis Reveals FOXA1 and Ku70\/Ku80 as Targets of Ivermectin in Prostate Cancer","volume":"13","author":"Lv S.","year":"2022","journal-title":"Cell Death & Disease"},{"key":"e_1_2_11_44_1","doi-asserted-by":"crossref","first-page":"34034","DOI":"10.1038\/srep34034","article-title":"Up\u2010Regulation of miR\u201095\u20103p in Hepatocellular Carcinoma Promotes Tumorigenesis by Targeting p21 Expression","volume":"6","author":"Ye J.","year":"2016","journal-title":"Scientific Reports"},{"key":"e_1_2_11_45_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.18632\/aging.100934","article-title":"Apoptosis as Anticancer Mechanism: Function and Dysfunction of Its Modulators and Targeted Therapeutic Strategies","volume":"8","author":"Pistritto G.","year":"2016","journal-title":"Aging (Albany NY)"},{"key":"e_1_2_11_46_1","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/cbdd.13860","article-title":"Caspase\u20103: A Primary Target for Natural and Synthetic Compounds for Cancer Therapy","volume":"98","author":"Yadav P.","year":"2021","journal-title":"Chemical Biology & Drug Design"},{"key":"e_1_2_11_47_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40659-019-0242-7","article-title":"Ropivacaine Promotes Apoptosis of Hepatocellular Carcinoma Cells Through Damaging Mitochondria and Activating Caspase\u20103 Activity","volume":"52","author":"Wang W.","year":"2019","journal-title":"Biological Research"}],"container-title":["BioFactors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/iubmb.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/biof.70155","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iubmb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/biof.70155","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iubmb.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/biof.70155","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:49:16Z","timestamp":1790772556000},"score":1,"resource":{"primary":{"URL":"https:\/\/iubmb.onlinelibrary.wiley.com\/doi\/10.1002\/biof.70155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/biof.70155"],"URL":"https:\/\/doi.org\/10.1002\/biof.70155","archive":["Portico"],"relation":{},"ISSN":["0951-6433","1872-8081"],"issn-type":[{"value":"0951-6433","type":"print"},{"value":"1872-8081","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-07-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70155"}}