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Bortezomib (BTZ), a first\u2010line therapeutic agent, is highly effective in MM; however, resistance remains a significant clinical challenge. Our previous work implicated Solute Carrier Family 19 Member 1 (SLC19A1) in hypoxia and immune modulation, suggesting its potential role in malignant progression. Here, we found that SLC19A1 expression was elevated in MM patients, particularly in those with acquired resistance. Overexpression of SLC19A1 enhanced the proliferation and invasiveness of human myeloma cell lines but did not confer primary BTZ resistance. Using a continuous\u2010BTZ\u2010exposure model, we demonstrated that SLC19A1 overexpression mediated acquired resistance via chronic activation of the stimulator of interferon genes (STING) pathway. This sustained activation triggered the unfolded protein response, dysregulated the endoplasmic reticulum\u2013mitochondrial axis, and induced mitochondrial DNA (mtDNA) release. Treatment with the SLC19A1 inhibitor sulfasalazine or the STING inhibitor H\u2010151 reduced mtDNA release and restored BTZ sensitivity. These findings highlight SLC19A1 and STING signaling as potential therapeutic targets for overcoming acquired drug resistance in MM.<\/jats:p>","DOI":"10.1002\/cbin.70130","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T12:15:41Z","timestamp":1768911341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Solute Carrier Family 19 Member 1 Mediates Acquired Bortezomib Resistance in Multiple Myeloma Through Chronic Stimulator of Interferon Genes Activation and Mitochondrial DNA Release"],"prefix":"10.1002","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3783-3404","authenticated-orcid":false,"given":"Yixuan","family":"Chen","sequence":"first","affiliation":[{"name":"Laboratory of Hematology Guilin Medical University Guilin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9988-1412","authenticated-orcid":false,"given":"Xianyi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Guilin Medical University Guilin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4089-0364","authenticated-orcid":false,"given":"Mingxuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology Guilin Medical University Guilin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2662-8760","authenticated-orcid":false,"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology Guilin Medical University Guilin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7223-0604","authenticated-orcid":false,"given":"Xiaotao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Guilin Medical University Guilin China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0021820"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.372"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2022.0002"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001372"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-22-3015"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10112898"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00524-z"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17091433"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.190"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-020-0315-4"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph16050749"},{"key":"e_1_2_13_13_1","first-page":"3065","article-title":"Plasma Cell\u2010Derived mtDAMPs Activate the Macrophage STING Pathway, Promoting Myeloma Progression","volume":"141","author":"Jibril A.","year":"2023","journal-title":"Blood"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2023.08.025"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-00965-7"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics14010038"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2020.0057"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30206-6"},{"key":"e_1_2_13_19_1","doi-asserted-by":"crossref","unstructured":"Kuncman \u0141. 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