{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:00:10Z","timestamp":1790154010042,"version":"4.0.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite significant advancements in proteasome inhibitors and immunomodulatory drugs, multiple myeloma (MM) remains largely incurable due to persistent drug resistance and frequent relapse, highlighting an urgent need for novel therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed Multiple Myeloma Research Foundation and GEO datasets to identify genes associated with disease progression, prioritizing UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1) for functional validation. The impact of UAP1 on MM\u00a0cell growth was evaluated through both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      models. Integrated metabolomics and transcriptomics were employed to elucidate the underlying regulatory mechanisms. Furthermore, virtual screening of an FDA-approved drug library was performed to identify potential UAP1 expression suppressor, followed by experimental validation of the lead compound\u2019s efficacy\n                      <jats:italic>via<\/jats:italic>\n                      molecular docking, combination therapy analysis, and gene expression intervention.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>UAP1 was found to be overexpressed in MM patients and positively correlated with disease severity. UAP1 knockdown significantly suppressed MM\u00a0cell proliferation, and promoted apoptosis. Mechanistically, integrated multi-omics analysis revealed that this growth inhibition was driven by the dysregulation of protein biosynthesis, degradation, and amino acid metabolism. Virtual screening identified Rabeprazole (RAB) as a potent expression suppressor candidate. RAB effectively inhibited MM\u00a0cell growth by downregulating UAP1 expression and exhibited synergistic anti-myeloma effects when combined with the proteasome inhibitor bortezomib. Knockdown and overexpression experiments confirmed that UAP1 is a functional target of RAB.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings establish UAP1 as a critical driver of MM progression and a promising therapeutic target. Genetic or pharmacological inhibition of UAP1 expression\n                      <jats:italic>via<\/jats:italic>\n                      RAB disrupts essential metabolic pathways, thereby stunting tumor growth. This study provides preclinical evidence for repurposing RAB as a novel UAP1-targeted strategy, offering a potential avenue to sensitize the therapeutic efficacy of bortezomib and improve clinical outcomes for MM patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1884338","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T08:02:11Z","timestamp":1790150531000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting UAP1 with rabeprazole: a novel repurposed therapeutic strategy for multiple myeloma"],"prefix":"10.3389","volume":"17","author":[{"given":"Longhao","family":"Cheng","sequence":"first","affiliation":[{"name":"Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Cheng","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aijun","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, China-Japan Friendship Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Gong","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Department of Pharmacy, China-Japan Friendship Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.2165\/00003495-200969100-00007","article-title":"Rabeprazole: a review of its use in the management of gastric acid-related diseases in adults","volume":"69","author":"Baldwin","year":"2009","journal-title":"Drugs"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1016\/s0140-6736(20)30164-1","article-title":"Small molecules, big impact: 20 years of targeted therapy in oncology","volume":"395","author":"Bedard","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4134","DOI":"10.7150\/thno.42903","article-title":"Nrf2 and HIF1\u03b1 converge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells","volume":"10","author":"Bi","year":"2020","journal-title":"Theranostics"},{"key":"B4","doi-asserted-by":"publisher","first-page":"798272","DOI":"10.3389\/fphar.2022.798272","article-title":"Proton pump inhibitors and cancer: current state of play","volume":"13","author":"Bridoux","year":"2022","journal-title":"Front. 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