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Our previous research has demonstrated that proline metabolism plays a role in\n MM<\/jats:styled-content>\n progression and that inhibiting\n PYCR1<\/jats:styled-content>\n , the final enzyme in proline synthesis, enhances bortezomib sensitivity in\n MM<\/jats:styled-content>\n cells. Given the high expression of\n PYCR1<\/jats:styled-content>\n in bone marrow stromal cells (\n BMSCs<\/jats:styled-content>\n ), we sought to investigate the effects of\n PYCR1<\/jats:styled-content>\n inhibition in\n BMSCs<\/jats:styled-content>\n and its indirect influence on\n MM<\/jats:styled-content>\n cell metabolism and viability. Culturing\n MM<\/jats:styled-content>\n cells in conditioned medium (\n CM<\/jats:styled-content>\n ) of\n PYCR1<\/jats:styled-content>\n \u2010silenced\n BMSC<\/jats:styled-content>\n significantly impaired oxidative phosphorylation and sensitised\n MM<\/jats:styled-content>\n cells to bortezomib. Analysis of the\n CM<\/jats:styled-content>\n secretome revealed a reduction in activin A release. Proline and activin A supplementation were able to counteract\n MM<\/jats:styled-content>\n sensitivity to bortezomib. Combination therapy of the\n PYCR1<\/jats:styled-content>\n inhibitor pargyline and bortezomib reduced tumour load in a\n 3D<\/jats:styled-content>\n model and reduced serum activin A levels in\n 5TGM1<\/jats:styled-content>\n \u2010bearing mice. This study demonstrates the contribution of stromal cell metabolism to\n MM<\/jats:styled-content>\n progression. Inhibiting\n PYCR1<\/jats:styled-content>\n in\n BMSCs<\/jats:styled-content>\n leads to less activin A release, limits oxidative phosphorylation in\n MM<\/jats:styled-content>\n cells and enhances bortezomib efficacy.\n <\/jats:p>","DOI":"10.1002\/1878-0261.70120","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T11:41:10Z","timestamp":1757590870000},"page":"447-463","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PYCR1<\/scp>\n inhibition in bone marrow stromal cells enhances bortezomib sensitivity in multiple myeloma cells by altering their metabolism"],"prefix":"10.1002","volume":"20","author":[{"given":"Inge","family":"Oudaert","sequence":"first","affiliation":[{"name":"Department of Hematology and Immunology, Myeloma Centre Brussels, Translational Oncology Research Centre Vrije Universiteit Brussel (VUB) 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