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We investigated the effects of RXR agonists (LG100754, bexarotene, AGN194204, and LG101506) on lenalidomide\u2019s anti-myeloma activity, T cell functions, and the level of glucose and lipids in vivo. Genetic overexpression and CRISPR\/Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR-agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of RXR agonists and lenalidomide demonstrated synergistic activity in increasing CRBN expression and killing myeloma cells. Mechanistically, the RXR agonists reduced the binding of PPARs to the CRBN promoter, thereby relieving the repressor effect of PPARs on CRBN transcription. RXR agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co-administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of myeloma.<\/jats:p>","DOI":"10.3390\/cells12151993","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T11:13:06Z","timestamp":1691061186000},"page":"1993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["RXR Agonists Enhance Lenalidomide Anti-Myeloma Activity and T Cell Functions while Retaining Glucose-Lowering Effect"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-9917","authenticated-orcid":false,"given":"Jian","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobei","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parker","family":"Mathews","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yubin","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1038\/s41417-020-0176-9","article-title":"Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and\/or CD40","volume":"27","author":"Wenthe","year":"2020","journal-title":"Cancer Gene Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41408-021-00441-3","article-title":"Therapeutic outcome of early-phase clinical trials in multiple myeloma: A meta-analysis","volume":"11","author":"Frunt","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Faruq, O., Zhao, D., Shrestha, M., Vecchione, A., Zacksenhaus, E., and Chang, H. 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