{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T21:46:08Z","timestamp":1791755168008,"version":"4.3.4"},"reference-count":41,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mol Pain"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>\n                    Secondary plant metabolites are widely used in traditional and naturopathic medicine to treat pain, infection, and inflammation. The sesquiterpenoid zerumbone, derived from the edible ginger\n                    <jats:italic toggle=\"yes\">Zingiber zerumbet<\/jats:italic>\n                    , has been shown to exert analgesic, antioxidant, antitumoral, and antimicrobial effects in preclinical models, acting through multiple receptor systems including cannabinoid (CB) receptors, peroxisome proliferator-activated receptors, N-methyl-D-aspartate (NMDA) receptors, and the serotonergic system. Zerumbone also modulates inflammatory and nitric oxide\u2013cGMP\u2013K\n                    <jats:sup>+<\/jats:sup>\n                    ATP signaling pathways implicated in antiallodynic responses, yet its direct impact on nociceptor-associated ion channels like the Transient receptor potential vanilloid 1 (TRPV1) and the Twik-related spinal cord potassium channel (TRESK) in human cellular systems remains poorly characterized. In the present study, the antinociceptive properties of zerumbone were investigated in human HEK293-based and induced pluripotent stem cell (iPSC)-derived nociceptor models. Here, the zerumbone treatment reduced cell viability and proliferation in a concentration-dependent manner without altering TRPV1 or TRESK protein expression. Whole-cell patch-clamp recordings revealed that zerumbone reversibly inhibited TRESK-mediated outward potassium currents upon direct application, whereas bath-applied zerumbone increased outward currents, suggesting context-dependent modulation. In TRPV1-expressing HEK293 cells, SH-SY5Y neuroblastoma cells, and human iPSC-derived nociceptors, zerumbone reduced TRPV1-mediated ion currents and capsaicin-evoked calcium signals, indicating a direct or competitive inhibitory effect on TRPV1 activity. In iPSC-derived nociceptors, zerumbone decreased action potential firing at moderate depolarizing currents, shifted the resting membrane potential, and increased rheobase, consistent with reduced nociceptor excitability, while no significant changes in TRESK-mediated currents were detected. These data suggest that zerumbone attenuates human iPSC-derived nociceptor-like neuron excitability largely via TRPV1 inhibition, with a more complex, concentration- and application-method-dependent modulation of TRESK. The findings provide a mechanistic basis for the antiallodynic effects of zerumbone observed in rodent models and highlight the need for further studies in human-derived systems to clarify the precise channel-level interactions and their relevance to inflammatory and neuropathic pain.\n                  <\/jats:p>","DOI":"10.1177\/17448069261492873","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:17:22Z","timestamp":1791501442000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Zerumbone alleviates TRESK- and TRPV1-mediated ion currents and reduces excitability of human iPSC-derived nociceptor-like neurons"],"prefix":"10.1177","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3939-0458","authenticated-orcid":false,"given":"Naomi","family":"Hoerdler","sequence":"first","affiliation":[{"name":"Bielefeld University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3545-5711","authenticated-orcid":false,"given":"Angelique","family":"Grell","sequence":"additional","affiliation":[{"name":"Bielefeld University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saheli","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Bielefeld University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhard","family":"Wischmeyer","sequence":"additional","affiliation":[{"name":"Bielefeld University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice A.","family":"Nossek","sequence":"additional","affiliation":[{"name":"Bielefeld University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3027-6262","authenticated-orcid":false,"given":"Oliver","family":"Dr\u00e4ger","sequence":"additional","affiliation":[{"name":"Bielefeld University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/543216"},{"key":"e_1_3_7_3_2","doi-asserted-by":"publisher","DOI":"10.1055\/a-2219-9801"},{"key":"e_1_3_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2015.07.011"},{"key":"e_1_3_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2009.02.002"},{"key":"e_1_3_7_6_2","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S143024"},{"key":"e_1_3_7_7_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/563930"},{"key":"e_1_3_7_8_2","first-page":"4442","article-title":"Evaluation of acute toxicity and the effect of single injected doses of zerumbone on the kidney and liver functions in Sprague Dawley rats","author":"Ibrahim MY","year":"2010","unstructured":"Ibrahim MY. Evaluation of acute toxicity and the effect of single injected doses of zerumbone on the kidney and liver functions in Sprague Dawley rats. African Journal of Biotechnology 2010: 4442\u20134450.","journal-title":"African Journal of Biotechnology"},{"key":"e_1_3_7_9_2","first-page":"5","article-title":"Healthy Zerumbone: From Natural Sources to Strategies to Improve Its Bioavailability and Oral Administration","volume":"12","author":"Ib\u00e1\u00f1ez MD","year":"2022","unstructured":"Ib\u00e1\u00f1ez MD, S\u00e1nchez-Ballester NM, Bl\u00e1zquez MA. Healthy Zerumbone: From Natural Sources to Strategies to Improve Its Bioavailability and Oral Administration. Plants (Basel) 2022; 12: 5. https:\/\/doi.org\/10.3390\/plants12010005","journal-title":"Plants (Basel)"},{"key":"e_1_3_7_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26133849"},{"key":"e_1_3_7_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00092"},{"key":"e_1_3_7_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.08.052"},{"key":"e_1_3_7_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.652860"},{"key":"e_1_3_7_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules22040555"},{"key":"e_1_3_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80564-4"},{"key":"e_1_3_7_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/39807"},{"key":"e_1_3_7_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep12548"},{"key":"e_1_3_7_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2009"},{"key":"e_1_3_7_19_2","doi-asserted-by":"publisher","DOI":"10.1177\/0333102421989261"},{"key":"e_1_3_7_20_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP279203"},{"key":"e_1_3_7_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155206"},{"key":"e_1_3_7_22_2","article-title":"Formulation and Nanotechnology-Based Approaches for Solubility and Bioavailability Enhancement of Zerumbone","volume":"56","author":"Kesharwani SS","year":"2020","unstructured":"Kesharwani SS, Bhat GJ. Formulation and Nanotechnology-Based Approaches for Solubility and Bioavailability Enhancement of Zerumbone. Medicina (Kaunas) 2020; 56. https:\/\/doi.org\/10.3390\/medicina56110557","journal-title":"Medicina (Kaunas)"},{"key":"e_1_3_7_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-026-05174-3"},{"key":"e_1_3_7_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2249"},{"key":"e_1_3_7_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10060344"},{"key":"e_1_3_7_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_3_7_27_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.113.088997"},{"key":"e_1_3_7_28_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules30081742"},{"key":"e_1_3_7_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-021-01190-7"},{"key":"e_1_3_7_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbio.202400500"},{"key":"e_1_3_7_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-023-02603-5"},{"key":"e_1_3_7_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-024-02327-3"},{"key":"e_1_3_7_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.7b04472"},{"key":"e_1_3_7_34_2","doi-asserted-by":"publisher","DOI":"10.5114\/fn.2019.88458"},{"key":"e_1_3_7_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2013.00141"},{"key":"e_1_3_7_36_2","first-page":"339","article-title":"Natural Active Ingredients and TRPV1 Modulation: Focus on Key Chemical Moieties Involved in Ligand-Target Interaction","volume":"12","author":"Andrei C","year":"2023","unstructured":"Andrei C, Zanfirescu A, Ni\u021bulescu GM, et al. Natural Active Ingredients and TRPV1 Modulation: Focus on Key Chemical Moieties Involved in Ligand-Target Interaction. Plants (Basel) 2023; 12: 339. https:\/\/doi.org\/10.3390\/plants12020339","journal-title":"Plants (Basel)"},{"key":"e_1_3_7_37_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP279548"},{"key":"e_1_3_7_38_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25173880"},{"key":"e_1_3_7_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2011.05.043"},{"key":"e_1_3_7_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2010.00635.x"},{"key":"e_1_3_7_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2010.05.009"},{"key":"e_1_3_7_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2221-1691(11)60090-7"}],"container-title":["Molecular Pain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17448069261492873","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/17448069261492873","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17448069261492873","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T21:16:32Z","timestamp":1791753392000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/17448069261492873"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":41,"alternative-id":["10.1177\/17448069261492873"],"URL":"https:\/\/doi.org\/10.1177\/17448069261492873","relation":{},"ISSN":["1744-8069","1744-8069"],"issn-type":[{"value":"1744-8069","type":"print"},{"value":"1744-8069","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"article-number":"17448069261492873"}}