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Here, we showed that GABA levels are significantly elevated in the bone marrow (BM) liquid of patients with multiple myeloma (MM) compared to healthy donors (HDs). Moreover, BM GABA levels correlated with key clinical parameters, including plasma cell percentage, International Staging System (ISS) stage, and immunoglobulin subtype, highlighting its association with disease severity. Mechanistically, we identified glutamic acid decarboxylase 1 (GAD1) as a critical enzyme driving intracellular GABA production in MM cells, which promotes the survival and proliferation of MM cells. Additionally, GAD1-dependent GABA production supported MM progression by activating the GABA-B receptor, as demonstrated in vitro and in vivo, underscoring the pivotal role of this receptor axis. Further mechanistic investigations revealed that the GABA-B receptor axis enhances extracellular regulated kinases1\/2 (ERK1\/2) activity via cAMP downregulation, facilitating MM cell survival and proliferation. Taken together, our findings establish the GABA-B receptor\u2013ERK1\/2 axis as a central regulator of MM progression and propose it as a promising target for MM therapy.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf166","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T12:56:25Z","timestamp":1763211385000},"source":"Crossref","is-referenced-by-count":1,"title":["Gamma-aminobutyric acid-B receptor axis promotes proliferation and survival of multiple myeloma cells via enhancing ERK1\/2 activity"],"prefix":"10.1093","volume":"117","author":[{"given":"Wei","family":"Hu","sequence":"first","affiliation":[{"name":"Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China , Changshengxi Road 28#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5626-5333","authenticated-orcid":false,"given":"Chang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Third Xiangya Hospital, Central South University , Tongzipo Road 138#, Changsha, Hunan 410013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2986-7140","authenticated-orcid":false,"given":"Fen","family":"He","sequence":"additional","affiliation":[{"name":"Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China , Changshengxi Road 28#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2311-2413","authenticated-orcid":false,"given":"Hongyan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China , Changshengxi Road 28#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1720-2146","authenticated-orcid":false,"given":"Lijun","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China , Chuanshandadao Road 69#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8133-2972","authenticated-orcid":false,"given":"Ruixin","family":"Gao","sequence":"additional","affiliation":[{"name":"Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China , Changshengxi Road 28#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3631-5351","authenticated-orcid":false,"given":"Maoyou","family":"Lu","sequence":"additional","affiliation":[{"name":"Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China , Changshengxi Road 28#, Hengyang, Hunan 421001 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China , Changshengxi Road 28#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China , Changshengxi Road 28#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Hematology, The First Affiliated Hospital, Hengyang Medical School, University of South China , Chuanshandadao Road 69#, Hengyang, Hunan 421001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiong","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Hematology, The First Affiliated Hospital, Hengyang Medical School, University of South China , Chuanshandadao 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