{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:36Z","timestamp":1785422736103,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274018"],"award-info":[{"award-number":["82274018"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82274018"],"award-info":[{"award-number":["82274018"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bortezomib (BTZ), the first-generation proteasome inhibitor, has been approved for the treatment of relapsed, refractory, and newly diagnosed multiple myeloma. Despite its remarkable antitumor efficacy, BTZ treatment is severely limited by a high incidence of systemic adverse reactions, primarily due to its non-selective cytotoxicity toward rapidly dividing normal cells and its potent neurotoxic effects on peripheral neurons. Bortezomib-induced peripheral neurotoxicity (BIPN) manifests as neuropathic pain and sensory abnormalities, affecting up to 31% to 64% of patients and limiting BTZ\u2019s clinical use. Currently, the underlying mechanisms of BIPN are poorly understood. To evaluate the effects of BTZ on the functions of peripheral nerves in mice, we administered an intraperitoneal injection treatment for four weeks. Results indicated that BIPN caused mechanical allodynia, gait abnormalities, and pathological changes in myelin and axons in mice. This study confirms that BTZ upregulates the expression of the activating transcription factor 3 (ATF3), which in turn mediates the increased expression of the copper transporter SLC31A1, causing dysregulation of intracellular copper ion homeostasis and subsequent copper accumulation, and ultimately inducing the development of peripheral neurotoxicity. Elevated intracellular copper concentration exerts a dual effect: it directly promotes the oligomerization of Dihydrolipoamide S-acetyltransferase (DLAT) and concurrently damages the iron\u2013sulfur cluster protein ferredoxin 1 (FDX1), collectively triggering the onset of cuproptosis. Green tea has garnered attention for its rich content of catechins, with (\u2212)-Epigallocatechin Gallate (EGCG) being the most abundant catechin present. This study uncovers the molecular mechanism by which EGCG inhibits BTZ-induced cuproptosis through targeted regulation of copper homeostasis. Analyses demonstrate that EGCG significantly downregulates the expression of the copper transporter SLC31A1, thereby effectively suppressing transmembrane influx of extracellular copper ions. This intervention markedly reduces intracellular copper overload, eliciting a dual regulatory effect: on one hand, the decreased copper concentration directly inhibits the oligomerization of DLAT; on the other hand, it effectively protects the iron\u2013sulfur cluster protein FDX1 from damage. This study aims to systematically elucidate the molecular mechanisms underlying BIPN and to evaluate the therapeutic potential of EGCG in alleviating BIPN, offering a novel therapeutic strategy for the prevention and treatment of BIPN.<\/jats:p>","DOI":"10.3390\/ijms27083680","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T07:57:21Z","timestamp":1776758241000},"page":"3680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ATF3\/SLC31A1-Mediated Cuproptosis Contributes to Bortezomib-Induced Peripheral Neurotoxicity and Intervention by (\u2212)-Epigallocatechin Gallate"],"prefix":"10.3390","volume":"27","author":[{"given":"Yonghai","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabin","family":"Lu","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejing","family":"Feng","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"School of Medicine, Hangzhou City University, Hangzhou 310015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaojun","family":"He","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peihua","family":"Luo","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2248-5235","authenticated-orcid":false,"given":"Xiaochun","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Nanhu Brain-Computer Interface Institute, Hangzhou 311100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"ref_1","first-page":"859","article-title":"Bortezomib: A Review of its Use in Patients with Multiple Myeloma","volume":"69","author":"Curran","year":"2009","journal-title":"Adis Drug Eval."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pinto, V., Bergantim, R., Caires, H.R., Seca, H., Guimar\u00e3es, J.E., and Vasconcelos, M.H. 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