{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:10:13Z","timestamp":1787508613613,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["23K24189"],"award-info":[{"award-number":["23K24189"]}]},{"name":"Toyo University Top Priority Research Program","award":["2023T1"],"award-info":[{"award-number":["2023T1"]}]},{"name":"The Promotion and Mutual Aid Corporation"},{"name":"Grant-in-Aid for the Enryo Inoue Memorial"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer remains one of the leading causes of cancer-related mortality both in Japan and worldwide. Oxaliplatin (L-OHP) is a key chemotherapeutic agent used in the treatment of colorectal and other malignancies; however, its clinical use is often limited by the development of oxaliplatin-induced peripheral neuropathy (OIPN). In this study, we investigated ergothioneine (EGT), a natural antioxidant abundant in mushrooms, for its potential to mitigate OIPN without compromising the antitumor efficacy of L-OHP. Using the SH-SY5Y neuroblastoma cell line and differentiated neurons, we assessed the effects of EGT on L-OHP-induced apoptosis, oxidative stress, and axonal degeneration. We further evaluated whether EGT interferes with the anticancer activity of L-OHP using cultured cancer cell lines and a tumor-bearing mouse model. EGT suppressed L-OHP-induced apoptosis in neuronal cells and preserved axonal structures in differentiated neurons. Importantly, EGT had no adverse effect on the antitumor efficacy of L-OHP, as evidenced by unchanged cancer cell proliferation, tumor volume, and body weight in treated mice. These findings suggest that EGT may be a promising adjuvant for preventing OIPN while maintaining the therapeutic benefits of L-OHP.<\/jats:p>","DOI":"10.3390\/ijms262110263","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:14:02Z","timestamp":1761182042000},"page":"10263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ergothioneine Attenuates Oxaliplatin-Induced Peripheral Neuropathy Without Compromising Antitumor Efficacy"],"prefix":"10.3390","volume":"26","author":[{"given":"Takumu","family":"Yamada","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Graduate School of Science and Engineering, Toyo University, Saitama 350-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9278-6464","authenticated-orcid":false,"given":"Takumi","family":"Iwasawa","sequence":"additional","affiliation":[{"name":"Institution of Life Innovation Studies, Toyo University, Tokyo 115-8650, Japan"},{"name":"Shizuoka Medical Research Center for Disaster, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryohma","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"Shizuoka Medical Research Center for Disaster, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4190-8923","authenticated-orcid":false,"given":"Tomoaki","family":"Ito","sequence":"additional","affiliation":[{"name":"Shizuoka Medical Research Center for Disaster, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan"},{"name":"Department of Surgery, Juntendo University Shizuoka Hospital, Juntendo University School of Medicine, Shizuoka 410-2295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Graduate School of Science and Engineering, Toyo University, Saitama 350-8585, Japan"},{"name":"Institution of Life Innovation Studies, Toyo University, Tokyo 115-8650, Japan"},{"name":"Department of Nutrition Sciences, Graduate School of Health and Sports Sciences, Toyo University, Tokyo 115-8650, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1097\/COC.0b013e3181fe41ed","article-title":"Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005","volume":"34","author":"Cheng","year":"2011","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_2","first-page":"177","article-title":"Colorectal cancer statistics, 2017","volume":"67","author":"Siegel","year":"2017","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4540","DOI":"10.1021\/cr400460s","article-title":"Metallodrugs in medicinal inorganic chemistry","volume":"114","author":"Mjos","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1021\/acsbiomaterials.7b00921","article-title":"Platinum (II) complex-nuclear localization sequence peptide hybrid for overcoming platinum resistance in cancer therapy","volume":"4","author":"Wlodarczyk","year":"2018","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1186\/s13046-021-02141-z","article-title":"Targeting strategies for oxaliplatin-induced peripheral neuropathy: Clinical syndrome, molecular basis, and drug development","volume":"40","author":"Yang","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/jnc.14607","article-title":"Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy","volume":"148","author":"Fujita","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3109\/0284186X.2014.995775","article-title":"Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives","volume":"54","author":"Ewertz","year":"2015","journal-title":"Acta Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jpainsymman.2016.12.342","article-title":"Chemotherapy-Induced Neuropathy in Cancer Survivors","volume":"54","author":"Miaskowski","year":"2017","journal-title":"J. Pain Symptom Manag."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s11064-013-1192-z","article-title":"Intrathecal miR-96 inhibits Nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury","volume":"39","author":"Chen","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1213\/01.ane.0000204318.35194.ed","article-title":"Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy","volume":"102","author":"Siau","year":"2006","journal-title":"Anesth. Analg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6704","DOI":"10.1073\/pnas.1118058109","article-title":"Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current","volume":"109","author":"Sittl","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11199","DOI":"10.1073\/pnas.1305321110","article-title":"Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2","volume":"110","author":"Sprowl","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1158\/1535-7163.MCT-08-0840","article-title":"Platinum neurotoxicity pharmacogenetics","volume":"8","author":"McWhinney","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1634\/theoncologist.2014-0044","article-title":"Platinum-induced neurotoxicity and preventive strategies: Past, present, and future","volume":"20","author":"Avan","year":"2015","journal-title":"Oncologist"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.nbd.2010.11.017","article-title":"Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons","volume":"41","author":"Podratz","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1002\/ijc.24853","article-title":"Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma","volume":"126","author":"Lim","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0014-2999(00)00667-1","article-title":"The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons","volume":"406","author":"Adelsberger","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1200\/JCO.21.00608","article-title":"Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin Versus Transarterial Chemoembolization for Large Hepatocellular Carcinoma: A Randomized Phase III Trial","volume":"40","author":"Li","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.lfs.2018.07.006","article-title":"Ergothioneine ameliorates oxaliplatin-induced peripheral neuropathy in rats","volume":"207","author":"Nishida","year":"2018","journal-title":"Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/1873-3468.14310","article-title":"Diet-derived ergothioneine induces necroptosis in colorectal cancer cells by activating the SIRT3\/MLKL pathway","volume":"596","author":"Martino","year":"2022","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1016\/j.ypmed.2011.12.001","article-title":"The ergothioneine transporter controls and indicates ergothioneine activity\u2014A review","volume":"54","author":"Grundemann","year":"2012","journal-title":"Prev. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1080\/01635581.2019.1637005","article-title":"Are Ergothioneine Levels in Blood Associated with Chronic Peripheral Neuropathy in Colorectal Cancer Patients Who Underwent Chemotherapy?","volume":"72","author":"Winkels","year":"2020","journal-title":"Nutr. Cancer"},{"key":"ref_23","first-page":"e53193","article-title":"Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line","volume":"108","author":"Shipley","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Amro, Z., Collins-Praino, L.E., and Yool, A.J. (2024). Protective roles of peroxiporins AQP0 and AQP11 in human astrocyte and neuronal cell lines in response to oxidative and inflammatory stressors. Biosci. Rep., 44.","DOI":"10.1042\/BSR20231725"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/0002-9378(79)90708-7","article-title":"Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood","volume":"135","author":"Yoshioka","year":"1979","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_26","first-page":"4697","article-title":"Ergothioneine prevents endothelial dysfunction induced by mercury chloride","volume":"15","author":"Gokce","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112516","DOI":"10.1016\/j.yexcr.2021.112516","article-title":"Ergothioneine alleviates senescence of fibroblasts induced by UVB damage of keratinocytes via activation of the Nrf2\/HO-1 pathway and HSP70 in keratinocytes","volume":"400","author":"Ko","year":"2021","journal-title":"Exp. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e18761429387340","DOI":"10.2174\/0118761429387340250507055903","article-title":"Ergothioneine Suppresses Amyloid beta-Induced Tau Phosphorylation and Cytotoxicity by Inactivating Glycogen Synthase Kinase-3beta in Cultured Neurons","volume":"17","author":"Shibagaki","year":"2024","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115590","DOI":"10.1016\/j.foodres.2024.115590","article-title":"Ergothioneine exerts neuroprotective effects in Parkinson\u2019s disease: Targeting alpha-synuclein aggregation and oxidative stress","volume":"201","author":"Gao","year":"2025","journal-title":"Food Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1124\/jpet.111.181297","article-title":"Oxaliplatin transport mediated by organic cation\/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons","volume":"338","author":"Jong","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8847","DOI":"10.1158\/0008-5472.CAN-06-0769","article-title":"Organic cation transporters are determinants of oxaliplatin cytotoxicity","volume":"66","author":"Zhang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4661","DOI":"10.1158\/1078-0432.CCR-04-0137","article-title":"Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells","volume":"10","author":"Goli","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_33","first-page":"1297","article-title":"Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B","volume":"53","author":"Gianluca","year":"2013","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1479-5876-10-21","article-title":"Copper-transporting P-type adenosine triphosphatase (ATP7A) is associated with platinum-resistance in non-small cell lung cancer (NSCLC)","volume":"10","author":"Li","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_35","first-page":"43","article-title":"Role of copper transporters in the uptake and efflux of platinum containing drugs","volume":"234","author":"Roohangiz","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1002\/1873-3468.14269","article-title":"The ergothioneine transporter (ETT): Substrates and locations, an inventory","volume":"596","author":"Grundemann","year":"2022","journal-title":"FEBS Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1124\/dmd.110.032763","article-title":"Functional expression of carnitine\/organic cation transporter OCTN1\/SLC22A4 in mouse small intestine and liver","volume":"38","author":"Sugiura","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4601","DOI":"10.1172\/JCI136796","article-title":"Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice","volume":"130","author":"Huang","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3902","DOI":"10.1016\/j.fct.2012.08.021","article-title":"Ergothioneine protects against neuronal injury induced by beta-amyloid in mice","volume":"50","author":"Yang","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1186\/s12944-024-02382-9","article-title":"Ergothioneine ameliorates metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) by enhancing autophagy, inhibiting oxidative damage and inflammation","volume":"23","author":"Lv","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1177\/1091581816653375","article-title":"A Safety Evaluation of a Nature-Identical l-Ergothioneine in Sprague Dawley Rats","volume":"35","author":"Marone","year":"2016","journal-title":"Int. J. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Turck, D., Bresson, J.L., Burlingame, B., Dean, T., Fairweather-Tait, S., Heinonen, M., Hirsch-Ernst, K.I., and Mangelsdorf, I. (2017). Statement on the safety of synthetic l-ergothioneine as a novel food\u2014Supplementary dietary exposure and safety assessment for infants and young children, pregnant and breastfeeding women. EFSA J., 15, e05060.","DOI":"10.2903\/j.efsa.2017.5060"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e12393","DOI":"10.1111\/jpi.12393","article-title":"Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy","volume":"62","author":"Aparna","year":"2017","journal-title":"J. Pineal Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.redox.2014.01.006","article-title":"Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy","volume":"2","author":"Aparna","year":"2014","journal-title":"Redox Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.phrs.2018.09.031","article-title":"PARP inhibition in platinum-based chemotherapy: Chemopotentiation and neuroprotection","volume":"137","author":"Rachel","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.ymeth.2007.01.003","article-title":"The sulphorhodamine (SRB) assay and other approaches to testing plant extracts and derived com-pounds for activities related to reputed anticancer activity","volume":"42","author":"Houghton","year":"2007","journal-title":"Methods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e14829","DOI":"10.1111\/cns.14829","article-title":"Sex differences in PD-L1-induced analgesia in Paclitaxel-induced peripheral neuropathy mice depend on TRPV-1-based inhibition of GCRP","volume":"30","author":"Cao","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Johannes","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:18:17Z","timestamp":1761182297000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":49,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110263"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110263","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,22]]}}}