{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:12:26Z","timestamp":1788671546124,"version":"build-2803163510"},"reference-count":74,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["S10 OD036226-01"],"award-info":[{"award-number":["S10 OD036226-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004833","name":"New Jersey Commission on Science, Innovation and Technology","doi-asserted-by":"publisher","award":["PROD-00319650"],"award-info":[{"award-number":["PROD-00319650"]}],"id":[{"id":"10.13039\/100004833","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PROD-00319650"],"award-info":[{"award-number":["PROD-00319650"]}],"id":[{"id":"https:\/\/ror.org\/03wy2a142","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Triple-negative breast cancer (TNBC) remains a major cause of cancer mortality due to its aggressive behavior, metabolic adaptability, and high therapeutic resistance. Extracellular vesicles (EVs) within the tumor microenvironment contribute to tumor progression and metastasis by transferring pro-tumorigenic cargo. While conventional Tumor Treating Fields use high-frequency alternating fields to disrupt mitosis, low-energy triple-frequency bioelectromagnetic approaches remain poorly characterized. Methods: We evaluated a device\u2013drug strategy combining triple-frequency low-intensity electromagnetic stimulation (EMS2: 396 Hz, 285 Hz, 528 Hz) with the pleiotropic drug Fingolimod (FTY720). Treatments were tested in MDA-MB-231 and ARM-G breast cancer cells, with Paclitaxel as a positive control. Cell proliferation was assessed by MTS assay, and extracellular vesicles were isolated following individual and combination treatments. Quantitative LC-MS\/MS proteomics was used to characterize treatment-induced changes in EVs cargo. Results: EMS2 reduced proliferation in both cell lines and produced morphological changes consistent with altered cell-cycle progression. EMS2 alone triggered adaptive metabolic responses, whereas combination with Fingolimod suppressed these compensatory signatures. EVs proteomics revealed combination-specific alterations associated with mitochondrial stress, ER stress, NF-\u03baB suppression, and autophagy-associated pathways. The combination also reduced levels of metastasis- and stroma-associated proteins, including Mitogen-Activated Protein Kinase 12 (MAPK12) and collagen-associated ECM components (Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type VI Alpha 1 Chain (COL6A1), Collagen Type VI Alpha 3 Chain (COL6A3), and Matrilin 3 (MATN3)) in EVs. Bliss independence analysis identified a subset of metastasis-associated proteins suppressed in EVs beyond the level predicted by an additive model, an exploratory finding that will require further validation with dose\u2013response and functional assays. Conclusions: Combined triple-frequency EMS2 and Fingolimod treatment altered the extracellular vesicle proteome, inducing signatures consistent with mitochondrial and endoplasmic reticulum stress, metabolic disruption, and reduced levels of metastasis-associated and stromal\/ECM remodeling proteins, along with reduced proliferation. These findings suggest a coordinated anti-cancer effect of this tunable device\u2013drug strategy, warranting further functional and in vivo validation to confirm therapeutic potential.<\/jats:p>","DOI":"10.3390\/ph19091399","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:07:32Z","timestamp":1788538052000},"page":"1399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Triple-Frequency Electromagnetic Stimulation Combined with Fingolimod Reduces Breast Cancer Cell Proliferation and Metastasis-Associated Extracellular Vesicle Protein Levels"],"prefix":"10.3390","volume":"19","author":[{"given":"Greg","family":"Haroutunian","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Daniels","sequence":"additional","affiliation":[{"name":"New Neurons LLC., Cedar Knolls, NJ 07927, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Ashot","family":"Tsaghikian","sequence":"additional","affiliation":[{"name":"Data Processing and Field Engineering Corp., Glendale, CA 91214, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Caifeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Phaedon","family":"Zavras","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Svetlana","family":"Marukian","sequence":"additional","affiliation":[{"name":"FL106 Inc., c\/o Flagship Pioneering, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Haiyan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0700-5210","authenticated-orcid":false,"given":"Arevik","family":"Mosoian","sequence":"additional","affiliation":[{"name":"EnergyBioCode LLC., Cedar Knolls, NJ 07927, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103027","DOI":"10.1016\/j.jgo.2026.103027","article-title":"Efficacy of immunotherapy in older adults with triple-negative breast cancer: A systematic review","volume":"17","author":"Sha","year":"2026","journal-title":"J. Geriatr. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"218350","DOI":"10.1016\/j.canlet.2026.218350","article-title":"Reprogramming the Immune Microenvironment in Triple-Negative Breast Cancer with mRNA Therapeutics","volume":"645","author":"Verma","year":"2026","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"117929","DOI":"10.1016\/j.bcp.2026.117929","article-title":"Novel targeted therapies and immunological strategies for breast cancer treatment","volume":"250","author":"Mussa","year":"2026","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6045","DOI":"10.1021\/acs.jproteome.5c00553","article-title":"Comprehensive Proteomic Profiling of Triple-Negative Breast Cancer-Derived Small Extracellular Vesicles Unveiled PXDN and GGT5 as Novel Protein Markers Implicated in Oncogenic Signaling Networks","volume":"24","author":"Khraibah","year":"2025","journal-title":"J. Proteome Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e70941","DOI":"10.1002\/cam4.70941","article-title":"Role of Exosome in Solid Cancer Progression and Its Potential Therapeutics in Cancer Treatment","volume":"14","author":"Aakel","year":"2025","journal-title":"Cancer Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Egawa, M., Schmucker, E., Grimm, C., Gudermann, T., and Chubanov, V. (2024). Expression Profiling Identified TRPM7 and HER2 as Potential Targets for the Combined Treatment of Cancer Cells. Cells, 13.","DOI":"10.3390\/cells13211801"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Liu, K., Xu, S.H., Chen, Z., Zeng, Q.X., Li, Z.J., and Chen, Z.M. (2018). TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90alpha\/uPA\/MMP2 signaling pathway. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-5050-x"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lefebvre, T., Rybarczyk, P., Bretaudeau, C., Vanlaeys, A., Cousin, R., Brassart-Pasco, S., Chatelain, D., Dhennin-Duthille, I., Ouadid-Ahidouch, H., and Brassart, B. (2020). TRPM7\/RPSA Complex Regulates Pancreatic Cancer Cell Migration. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00549"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102640","DOI":"10.1016\/j.ceca.2022.102640","article-title":"Pharmacological agents selectively acting on the channel moieties of TRPM6 and TRPM7","volume":"106","author":"Rossig","year":"2022","journal-title":"Cell Calcium"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103514","DOI":"10.1016\/j.mtbio.2026.103514","article-title":"A tumor microenvironment-responsive calcium overload nanoplatform inducing PANoptosis for enhanced cancer immunotherapy","volume":"40","author":"Tong","year":"2026","journal-title":"Mater. Today Bio"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2478\/raon-2023-0044","article-title":"A review of tumor treating fields (TTFields): Advancements in clinical applications and mechanistic insights","volume":"57","author":"Li","year":"2023","journal-title":"Radiol. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1002\/ijc.70408","article-title":"Efficacy and immunogenic effects of Tumor Treating Fields (TTFields) in preclinical models of pancreatic ductal adenocarcinoma, with and without gemcitabine\/nab-paclitaxel","volume":"158","author":"Kan","year":"2026","journal-title":"Int. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/s41420-022-01206-y","article-title":"The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy","volume":"8","author":"Tanzhu","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"oyae227","DOI":"10.1093\/oncolo\/oyae227","article-title":"Recent advances in Tumor Treating Fields (TTFields) therapy for glioblastoma","volume":"30","author":"Khagi","year":"2025","journal-title":"Oncologist"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1093\/rpd\/ncaf099","article-title":"Effects of 50 Hz extremely low-frequency magnetic field exposure on proliferative activity in cancer cells: An in vitro study","volume":"201","author":"Tekam","year":"2025","journal-title":"Radiat. Prot. Dosim."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.bbamcr.2019.05.006","article-title":"The extremely low frequency electromagnetic stimulation selective for cancer cells elicits growth arrest through a metabolic shift","volume":"1866","author":"Bergandi","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/bem.22401","article-title":"Electromagnetic Fields Generated by the IteraCoil Device Differentiate Mesenchymal Stem Progenitor Cells Into the Osteogenic Lineage","volume":"43","author":"Haroutunian","year":"2022","journal-title":"Bioelectromagnetics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1159\/000335795","article-title":"High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: Correlation with pathological parameters","volume":"28","author":"Gautier","year":"2011","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"C493","DOI":"10.1152\/ajpcell.00624.2008","article-title":"Evidence that TRPM7 is required for breast cancer cell proliferation","volume":"297","author":"Guilbert","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cordier, C., Prevarskaya, N., and Lehen\u2019kyi, V. (2021). TRPM7 Ion Channel: Oncogenic Roles and Therapeutic Potential in Breast Cancer. Cancers, 13.","DOI":"10.3390\/cancers13246322"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e23872","DOI":"10.1096\/fj.202401277R","article-title":"FTY720\/Fingolimod mitigates paclitaxel-induced Sparcl1-driven neuropathic pain and breast cancer progression","volume":"38","author":"Singh","year":"2024","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.2147\/DDDT.S293876","article-title":"FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4(+) T Lymphocytes","volume":"15","author":"Zhu","year":"2021","journal-title":"Drug Des. Devel Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e202313419","DOI":"10.1085\/jgp.202313419","article-title":"Analogs of FTY720 inhibit TRPM7 but not S1PRs and exert multimodal anti-inflammatory effects","volume":"156","author":"Busey","year":"2024","journal-title":"J. Gen. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mosoyan, G., Nagi, C., Marukian, S., Teixeira, A., Simonian, A., Resnick-Silverman, L., DiFeo, A., Johnston, D., Reynolds, S.R., and Roses, D.F. (2013). Multiple breast cancer cell-lines derived from a single tumor differ in their molecular characteristics and tumorigenic potential. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055145"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1038\/s42003-022-04077-2","article-title":"Voltage imaging reveals the dynamic electrical signatures of human breast cancer cells","volume":"5","author":"Quicke","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"573","DOI":"10.5732\/cjc.013.10177","article-title":"Targeted treatment of cancer with radiofrequency electromagnetic fields amplitude-modulated at tumor-specific frequencies","volume":"32","author":"Zimmerman","year":"2013","journal-title":"Chin. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"pe2","DOI":"10.1091\/mbc.E23-08-0312","article-title":"Bioelectricity is a universal multifaced signaling cue in living organisms","volume":"36","author":"Zhang","year":"2025","journal-title":"Mol. Biol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1109\/RBME.2017.2765282","article-title":"A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred From Computational Modeling","volume":"11","author":"Wenger","year":"2018","journal-title":"IEEE Rev. Biomed. Eng."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3288","DOI":"10.1158\/0008-5472.CAN-04-0083","article-title":"Disruption of cancer cell replication by alternating electric fields","volume":"64","author":"Kirson","year":"2004","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s12935-023-02959-x","article-title":"Optimization of tumor-treating field therapy for triple-negative breast cancer cells in vitro via frequency modulation","volume":"23","author":"Smothers","year":"2023","journal-title":"Cancer Cell Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/bem.22096","article-title":"Exposure to a specific time-varying electromagnetic field inhibits cell proliferation via cAMP and ERK signaling in cancer cells","volume":"39","author":"Buckner","year":"2018","journal-title":"Bioelectromagnetics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"322","DOI":"10.62347\/LXJH5896","article-title":"Tumor-treating fields and concurrent cisplatin: An in vitro demonstration of efficacy in triple-negative breast cancer","volume":"15","author":"Smothers","year":"2025","journal-title":"Am. J. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1080\/15368378.2021.1995872","article-title":"Effects of repeated exposure to 50 Hz electromagnetic field on breast cancer cells","volume":"41","author":"Abdolmaleki","year":"2022","journal-title":"Electromagn. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1002\/(SICI)1521-186X(1997)18:8<541::AID-BEM2>3.0.CO;2-2","article-title":"Responses of human MG-63 osteosarcoma cell line and human osteoblast-like cells to pulsed electromagnetic fields","volume":"18","author":"Sollazzo","year":"1997","journal-title":"Bioelectromagnetics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/bem.22031","article-title":"The effects of electromagnetic fields on B16-BL6 cells are dependent on their spatial and temporal character","volume":"38","author":"Buckner","year":"2017","journal-title":"Bioelectromagnetics"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Carrieri, F.A., Smack, C., Siddiqui, I., Kleinberg, L.R., and Tran, P.T. (2020). Tumor Treating Fields: At the Crossroads Between Physics and Biology for Cancer Treatment. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.575992"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18046","DOI":"10.1038\/srep18046","article-title":"Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells","volume":"5","author":"Giladi","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1007\/s12672-023-00647-w","article-title":"Efficacy and selectivity of tumor-treating field therapy for triple-negative breast cancer cells via in-house delivery device","volume":"14","author":"Smothers","year":"2023","journal-title":"Discov. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4250","DOI":"10.1158\/0008-5472.CAN-11-3863","article-title":"TRPM7 is required for breast tumor cell metastasis","volume":"72","author":"Middelbeek","year":"2012","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1111\/bph.12012","article-title":"Sphingosine and FTY720 are potent inhibitors of the transient receptor potential melastatin 7 (TRPM7) channels","volume":"168","author":"Qin","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ikarashi, M., Tsuchida, J., Nagahashi, M., Takeuchi, S., Moro, K., Toshikawa, C., Abe, S., Ichikawa, H., Shimada, Y., and Sakata, J. (2021). Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413367"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s13058-017-0882-x","article-title":"Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade","volume":"19","author":"Martin","year":"2017","journal-title":"Breast Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hirata, N., Yamada, S., Yanagida, S., Ono, A., and Kanda, Y. (2021). FTY720 Inhibits Expansion of Breast Cancer Stem Cells via PP2A Activation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147259"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Sojka, D.R., Hasterok, S., Vydra, N., Toma-Jonik, A., Wieczorek, A., Gogler-Piglowska, A., and Scieglinska, D. (2021). Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A. Cells, 10.","DOI":"10.3390\/cells10061418"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"106246","DOI":"10.1016\/j.msard.2024.106246","article-title":"Whole blood concentrations of fingolimod and its pharmacologically active metabolite fingolimod phosphate obtained during routine health care of patients with multiple sclerosis","volume":"93","author":"Kacirova","year":"2025","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1084\/jem.20090525","article-title":"T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow","volume":"206","author":"Jenne","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1007\/s13311-021-01078-7","article-title":"Fingolimod Therapy in Multiple Sclerosis Leads to the Enrichment of a Subpopulation of Aged NK Cells","volume":"18","author":"Schwichtenberg","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41598-019-57114-2","article-title":"Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis","volume":"10","author":"Ghadiri","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10723","DOI":"10.1080\/21655979.2021.2002499","article-title":"RASA4 inhibits the HIFalpha signaling pathway to suppress proliferation of cervical cancer cells","volume":"12","author":"Chen","year":"2021","journal-title":"Bioengineered"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"107367","DOI":"10.1016\/j.bpc.2024.107367","article-title":"Fifty-hertz magnetic fields induce DNA damage through activating mPTP associated mitochondrial permeability transition in senescent human fetal lung fibroblasts","volume":"318","author":"Sun","year":"2025","journal-title":"Biophys. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Shreeya, T., Ansari, M.S., Kumar, P., Saifi, M., Shati, A.A., Alfaifi, M.Y., and Elbehairi, S.E.I. (2023). Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases. Front. Aging, 4.","DOI":"10.3389\/fragi.2023.1292053"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"70","DOI":"10.4103\/ctm.ctm_22_18","article-title":"Senescence and Cancer","volume":"4","author":"Zeng","year":"2018","journal-title":"Cancer Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9861","DOI":"10.2147\/OTT.S216138","article-title":"TNIP1 Inhibits Proliferation and Promotes Apoptosis in Clear Cell Renal Carcinoma Through Targeting C\/Ebpbeta","volume":"12","author":"Yang","year":"2019","journal-title":"Onco Targets Ther."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Bunker, E.N., Fischer, T.D., Zhu, P.P., Le Guerroue, F., and Youle, R.J. (2025). TNIP1 and Autophagy Receptors regulate STING Signaling. bioRxiv.","DOI":"10.1101\/2025.04.21.649822"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.biosystems.2012.04.005","article-title":"Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning","volume":"109","author":"Levin","year":"2012","journal-title":"Biosystems"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1016\/j.cell.2021.02.034","article-title":"Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer","volume":"184","author":"Levin","year":"2021","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Pantelis, P., Theocharous, G., Veroutis, D., Vagena, I.A., Polyzou, A., Thanos, D.F., Kyrodimos, E., Kotsinas, A., Evangelou, K., and Lagopati, N. (2024). Pulsed Electromagnetic Fields (PEMFs) Trigger Cell Death and Senescence in Cancer Cells. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202401.1760.v1"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Nadezhdin, K.D., Neuberger, A., and Sobolevsky, A.I. (Worldwide Protein Data Bank, 2024). Cryo-EM structure of TRPM7 in GDN detergent in complex with inhibitor VER155008 in closed state, Worldwide Protein Data Bank.","DOI":"10.2210\/pdb8si7\/pdb"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"797","DOI":"10.4161\/cbt.28556","article-title":"Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro","volume":"15","author":"Marvaso","year":"2014","journal-title":"Cancer Biol. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Pina, M.A., Ozyurt, R., Mao, W., Yang, H., Santiago-O\u2019Farrill, J.M., Lu, Z., and Bast, R.C. (2026). Targeting SIK2 with GRN-300 Potentiates Paclitaxel Efficacy in Triple-Negative Breast Cancer. Cancers, 18.","DOI":"10.3390\/cancers18111843"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"103934","DOI":"10.1016\/j.autrev.2025.103934","article-title":"The effect of Sphingosine-1-phosphate receptor modulator treatment on leukocyte subsets across different clinical indications: A systematic review","volume":"24","author":"Nikolakis","year":"2025","journal-title":"Autoimmun. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"ar17","DOI":"10.1091\/mbc.E25-04-0190","article-title":"TNIP1 and autophagy receptors regulate STING signaling","volume":"37","author":"Bunker","year":"2026","journal-title":"Mol. Biol. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Zhou, J., Rasmussen, N.L., Olsvik, H.L., Akimov, V., Hu, Z., Evjen, G., Kaeser-Pebernard, S., Sankar, D.S., Roubaty, C., and Verlhac, P. (2023). TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1. J. Cell Biol., 222.","DOI":"10.1083\/jcb.202108144"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00280-009-1194-3","article-title":"A novel, small molecule inhibitor of Hsc70\/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells","volume":"66","author":"Massey","year":"2010","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1089\/ten.tea.2012.0091","article-title":"Mesenchymal stem cell osteodifferentiation in response to alternating electric current","volume":"19","author":"Creecy","year":"2013","journal-title":"Tissue Eng. Part A"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/jor.23059","article-title":"Synergistic effect of exogeneous and endogeneous electrostimulation on osteogenic differentiation of human mesenchymal stem cells seeded on silk scaffolds","volume":"34","author":"Cakmak","year":"2016","journal-title":"J. Orthop. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1475-925X-10-9","article-title":"Osteoblastic differentiation and stress response of human mesenchymal stem cells exposed to alternating current electric fields","volume":"10","author":"Rice","year":"2011","journal-title":"Biomed. Eng. Online"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1089\/ten.tec.2009.0751","article-title":"Application of low-frequency alternating current electric fields via interdigitated electrodes: Effects on cellular viability, cytoplasmic calcium, and osteogenic differentiation of human adipose-derived stem cells","volume":"16","author":"McCullen","year":"2010","journal-title":"Tissue Eng. Part C Methods"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.actbio.2015.12.024","article-title":"Electrical stimulation of adipose-derived mesenchymal stem cells in conductive scaffolds and the roles of voltage-gated ion channels","volume":"32","author":"Zhang","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Xu, A., Wang, Q., and Lin, T. (2020). Low-Frequency Magnetic Fields (LF-MFs) Inhibit Proliferation by Triggering Apoptosis and Altering Cell Cycle Distribution in Breast Cancer Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082952"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Crocetti, S., Beyer, C., Schade, G., Egli, M., Frohlich, J., and Franco-Obregon, A. (2013). Low intensity and frequency pulsed electromagnetic fields selectively impair breast cancer cell viability. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072944"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/s41596-018-0082-x","article-title":"Single-pot, solid-phase-enhanced sample preparation for proteomics experiments","volume":"14","author":"Hughes","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1074\/mcp.RA119.001587","article-title":"Analysis of Brain and Cerebrospinal Fluid from Mouse Models of the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Changes in the Lysosomal Proteome","volume":"18","author":"Sleat","year":"2019","journal-title":"Mol. Cell. Proteom."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1399\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:22:00Z","timestamp":1788668520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1399"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":74,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ph19091399"],"URL":"https:\/\/doi.org\/10.3390\/ph19091399","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}