{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T18:27:51Z","timestamp":1776364071149,"version":"3.51.2"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of Chongqing","award":["CSTB2023NSCQ-MSX0563"],"award-info":[{"award-number":["CSTB2023NSCQ-MSX0563"]}]},{"name":"Natural Science Foundation of Chongqing","award":["21827812"],"award-info":[{"award-number":["21827812"]}]},{"DOI":"10.13039\/501100001809","name":"National Major Scientific Research Instrument Development Project of NSFC","doi-asserted-by":"publisher","award":["CSTB2023NSCQ-MSX0563"],"award-info":[{"award-number":["CSTB2023NSCQ-MSX0563"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Major Scientific Research Instrument Development Project of NSFC","doi-asserted-by":"publisher","award":["21827812"],"award-info":[{"award-number":["21827812"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The interaction between molecular targeted therapy drugs and target proteins is crucial with regard to the drugs\u2019 anti-tumor effects. Electric fields can change the structure of proteins, which determines the interaction between drugs and proteins. However, the regulation of the interaction between drugs and target proteins and the anti-tumor effects of electric fields have not been studied thoroughly. Here, we explored how electric fields enhance the inhibition of regorafenib with regard to the activity, invasion, and metastasis of hepatocellular carcinoma cells. We found that electric fields lead to an increase in the normal (adhesion) and transverse (friction) interaction forces between regorafenib and VEGFR2. In single molecule pair interactions, there are changes in specific and nonspecific forces. Hydrogen bonds, hydrophobic interactions, and van der Waals forces are the main influencing factors. Importantly, the increase in the adhesion force and friction force between regorafenib and VEGFR2 caused by electric fields is related to the activity and migration ability of hepatocellular carcinoma cells. The morphological changes in VEGFR2 prove that electric fields regulate protein conformation. Overall, our work proves the drug\u2013protein mechanical mechanism by which electric fields enhance the anti-tumor effect of regorafenib and provides insights into the application of electric fields in clinical tumor treatment.<\/jats:p>","DOI":"10.3390\/biom15010042","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T11:24:19Z","timestamp":1735730659000},"page":"42","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effect of Electric Fields on the Mechanical Mechanism of Regorafenib\u2013VEGFR2 Interaction to Enhance Inhibition of Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Yichen","family":"Tian","sequence":"first","affiliation":[{"name":"Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China"},{"name":"Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fenghui","family":"Liao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongrong","family":"Lei","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China"},{"name":"Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuna","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Xia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing 400038, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0459-7145","authenticated-orcid":false,"given":"Jianhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","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_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S1470-2045(21)00604-5","article-title":"Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): A randomised, multicentre, open-label, phase 3 trial","volume":"23","author":"Yau","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/S0140-6736(23)00961-3","article-title":"Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): A randomised, open-label, international phase 3 study","volume":"402","author":"Qin","year":"2023","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41591-024-02824-y","article-title":"Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: The phase 2 RENOBATE trial","volume":"30","author":"Kim","year":"2024","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/s41392-023-01469-6","article-title":"Adverse effects of tyrosine kinase inhibitors in cancer therapy: Pathophysiology, mechanisms and clinical management","volume":"8","author":"Sharma","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41594-019-0358-z","article-title":"Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases","volume":"27","author":"Persky","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1038\/nsmb.2168","article-title":"Mechanistic insights into the activation of oncogenic forms of EGF receptor","volume":"18","author":"Wang","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1038\/s41467-024-45247-6","article-title":"The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma","volume":"15","author":"Spahn","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1038\/nsmb.3470","article-title":"Atomic view of the energy landscape in the allosteric regulation of Abl kinase","volume":"24","author":"Saleh","year":"2017","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_10","first-page":"35","article-title":"Gatekeeper Mutations Mediate Resistance to BRAF-Targeted Therapies","volume":"2","author":"Steven","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Shao, D., Xu, P., and Jiang, Z. (2021). Effects of an Electric Field on the Conformational Transition of the Protein: Pulsed and Oscillating Electric Fields with Different Frequencies. Polymers, 14.","DOI":"10.3390\/polym14010123"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"109826","DOI":"10.1016\/j.foodhyd.2024.109826","article-title":"Extending the freshness of tilapia surimi with pulsed electric field modified pea protein isolate-EGCG complex","volume":"151","author":"Han","year":"2024","journal-title":"Food Hydrocoll."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1038\/s41467-021-25478-7","article-title":"The SARS-CoV-2 spike protein is vulnerable to moderate electric fields","volume":"12","author":"Arbeitman","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8502","DOI":"10.1021\/acs.jmedchem.0c00891","article-title":"Structural Basis of AZD9291 Selectivity for EGFR T790M","volume":"63","author":"Yan","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/s41594-022-00860-1","article-title":"Structural basis for Na(V)1.7 inhibition by pore blockers","volume":"29","author":"Zhang","year":"2022","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_16","first-page":"136ra70","article-title":"Kinase-Impaired BRAF Mutations in Lung Cancer Confer Sensitivity to Dasatinib","volume":"4","author":"Banibrata","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1038\/s41467-019-10581-7","article-title":"Electric field dynamics in the brain during multi-electrode transcranial electric stimulation","volume":"10","author":"Alekseichuk","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1002\/hed.27298","article-title":"Tumor treating fields as novel combination partner in the multimodal treatment of head and neck cancer","volume":"45","author":"Regnery","year":"2023","journal-title":"Head Neck"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ijbiomac.2019.05.008","article-title":"Evaluating the effect of aminoglycosides on the interaction between bovine serum albumins by atomic force microscopy","volume":"134","author":"Wang","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1038\/s41375-021-01283-5","article-title":"Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance","volume":"35","author":"Song","year":"2021","journal-title":"Leukemia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1021\/jacsau.3c00142","article-title":"S373P Mutation Stabilizes the Receptor-Binding Domain of the Spike Protein in Omicron and Promotes Binding","volume":"3","author":"Zheng","year":"2023","journal-title":"JACS Au"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1038\/s41594-024-01260-3","article-title":"HS-AFM single-molecule structural biology uncovers basis of transporter wanderlust kinetics","volume":"31","author":"Jiang","year":"2024","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7872","DOI":"10.1021\/acsnano.3c01185","article-title":"Two-Molecule Force Spectroscopy on Proteins","volume":"17","author":"Zuo","year":"2023","journal-title":"ACS Nano"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, M., Dang, D., Liu, L., Xi, N., and Wang, Y. (2017). Imaging and Force Recognition of Single Molecular Behaviors Using Atomic Force Microscopy. Sensors, 17.","DOI":"10.3390\/s17010200"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ivanov, Y.D., Pleshakova, T.O., Shumov, I.D., Kozlov, A.F., Ivanova, I.A., Valueva, A.A., Tatur, V.Y., Smelov, M.V., Ivanova, N.D., and Ziborov, V.S. (2020). AFM Imaging of Protein Aggregation in Studying the Impact of Knotted Electromagnetic Field on A Peroxidase. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-65888-z"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/nm.2537","article-title":"Tumor angiogenesis: Molecular pathways and therapeutic targets","volume":"17","author":"Weis","year":"2011","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/ncponc0342","article-title":"Angiogenic inhibitors: A new therapeutic strategy in oncology","volume":"2","author":"Gasparini","year":"2005","journal-title":"Nat. Clin. Pract. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.1038\/s41467-024-48144-0","article-title":"Mutation characteristics and molecular evolution of ovarian metastasis from gastric cancer and potential biomarkers for paclitaxel treatment","volume":"15","author":"Yu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41568-021-00427-0","article-title":"Towards targeting of shared mechanisms of cancer metastasis and therapy resistance","volume":"22","author":"Weiss","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1038\/s41551-023-01080-8","article-title":"Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission","volume":"7","author":"Zhang","year":"2023","journal-title":"Nat. Biomed. Eng."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2019.02.018","article-title":"Identification of a mechanogenetic link between substrate stiffness and chemotherapeutic response in breast cancer","volume":"202","author":"Medina","year":"2019","journal-title":"Biomaterials"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2106196","DOI":"10.1002\/smll.202106196","article-title":"High-Throughput DNA Tensioner Platform for Interrogating Mechanical Heterogeneity of Single Living Cells","volume":"18","author":"Hang","year":"2022","journal-title":"Small"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/s41563-023-01716-9","article-title":"Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer","volume":"23","author":"Chang","year":"2023","journal-title":"Nat. Mater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1038\/s41418-020-00643-5","article-title":"YAP\u2013TEAD1 control of cytoskeleton dynamics and intracellular tension guides human pluripotent stem cell mesoderm specification","volume":"28","author":"Pagliari","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1038\/s41467-017-02243-3","article-title":"Snail determines the therapeutic response to mTOR kinase inhibitors by transcriptional repression of 4E-BP1","volume":"8","author":"Wang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14053","DOI":"10.1038\/ncomms14053","article-title":"HOPX hypermethylation promotes metastasis via activating SNAIL transcription in nasopharyngeal carcinoma","volume":"8","author":"Ren","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sculthorpe, D.J., Denton, A., Fadhil, W., Rusnita, D., Ilyas, M., and Mukherjee, A. (2024). High \u03b1-SMA expression in the tumor stroma is associated with adverse clinical parameters in mismatch repair\u2013proficient colorectal cancers only. Am. J. Clin. Pathol., aqae145.","DOI":"10.1093\/ajcp\/aqae145"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nature20571","article-title":"Electric-field-stimulated protein mechanics","volume":"540","author":"Hekstra","year":"2016","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1021\/cm960556e","article-title":"Direct Measurement of the Adhesion and Friction of Smooth C60 Surfaces","volume":"9","author":"Gustavo","year":"1997","journal-title":"Chem. Mater."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.carbon.2023.01.050","article-title":"Capillary adhesion governs the friction behavior of electrochemically corroded polycrystalline diamond","volume":"205","author":"Xiao","year":"2023","journal-title":"Carbon"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Anderson, M.S. (2023). Lateral force separation of biopolymers using an atomic force microscope. Biomicrofluidics, 17.","DOI":"10.1063\/5.0153116"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4111","DOI":"10.1021\/acs.nanolett.2c04632","article-title":"Anisotropic Friction in a Ligand-Protein Complex","volume":"23","author":"Cai","year":"2023","journal-title":"Nano Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/nsb911","article-title":"Loading direction regulates the affinity of ADP for kinesin","volume":"10","author":"Uemura","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"eabo1461","DOI":"10.1126\/sciadv.abo1461","article-title":"Force- and cell state\u2013dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry","volume":"8","author":"Yao","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41594-023-01122-4","article-title":"Mechanical disengagement of the cohesin ring","volume":"31","author":"Richeldi","year":"2024","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Tian, S., Wang, C., Zhou, Y., Feng, Y., Yao, X., Ge, C., He, M., Yang, G., and Jin, K. (2019). Effect of mechanical force on domain switching in BiFeO3 ultrathin films. Science China Physics, Mechanics & Astronomy, Science China Press.","DOI":"10.1007\/s11433-019-9415-9"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"31791","DOI":"10.1039\/D3CP04351G","article-title":"Single-molecule scale quantification reveals interactions underlying protein-protein interface: From forces to non-covalent bonds","volume":"25","author":"Sun","year":"2023","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s13046-024-03106-8","article-title":"Combination of dual JAK\/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer","volume":"43","author":"Bajpai","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/42\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T15:23:01Z","timestamp":1759850581000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/1\/42"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["biom15010042"],"URL":"https:\/\/doi.org\/10.3390\/biom15010042","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,1]]}}}