PYCR1 inhibition in bone marrow stromal cells enhances bortezomib sensitivity in multiple myeloma cells by altering their metabolism

Despite significant advancements, multiple myeloma ( MM ) remains incurable, largely due to drug resistance. Our previous research has demonstrated that proline metabolism plays a role in MM progression and that inhibiting PYCR1 , the final enzyme in proline synthesis, enhances bortezomib sensitivity in MM cells. Given the high expression of PYCR1 in bone marrow stromal cells ( BMSCs ), we sought to investigate the effects of PYCR1 inhibition in BMSCs and its indirect influence on MM cell metabolism and viability. Culturing MM cells in conditioned medium ( CM ) of PYCR1 ‐silenced BMSC significantly impaired oxidative phosphorylation and sensitised MM cells to bortezomib. Analysis of the CM secretome revealed a reduction in activin A release. Proline and activin A supplementation were able to counteract MM sensitivity to bortezomib. Combination therapy of the PYCR1 inhibitor pargyline and bortezomib reduced tumour load in a 3D model and reduced serum activin A levels in 5TGM1 ‐bearing mice. This study demonstrates the contribution of stromal cell metabolism to MM progression. Inhibiting PYCR1 in BMSCs leads to less activin A release, limits oxidative phosphorylation in MM cells and enhances bortezomib efficacy.