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Immunol."],"abstract":"<jats:p>Chemotherapeutic proteasomal inhibitors Bortezomib (BTZ, reversible inhibitor) and Carfilzomib (CFZ, irreversible inhibitor) are established frontline therapies for multiple myeloma (MM). However, their on-target versus off-target bystander effects in the bloodstream are not clearly known. To elucidate the acute adverse effects of intravenous proteasomal inhibition, we studied some of the key cell types of blood microvasculature: barrier endothelial cells, peripheral blood mononuclear cells (PBMC)s and multiple myeloma (MM1.S) cells. BTZ, but not CFZ, is cytotoxic to microvascular endothelial cells from lung or brain at 100 nM concentration. In human pulmonary microvascular endothelial cell (HPMEC)s, BTZ induces multiple stress pathways: proteotoxic stress, endoplasmic reticulum (ER) stress, and mitochondrial reactive oxygen species (ROS) accumulation. This is associated with activation of apoptotic caspase (CASP)9 (mediator of intrinsic-apoptosis), CASP8 (mediator of extrinsic-apoptosis) and CASP3 (terminal executioner of apoptosis). BTZ-treated HPMECs significantly die and lose vascular barrier function by 24 hours post treatment. These events occur independently of external cues. When we compared 100 nM of BTZ to 250 nM of CFZ (1:2.5 being the ratio of concentration in patients), both compounds elicit comparable cytotoxicity, but elevated ER stress and apoptotic markers are driven by BTZ. Both compounds kill multiple myeloma cells comparably. PBMCs resist drug-mediated changes. Neither inhibitor elicits inflammatory response from HPMECs, MM1.S cells or PBMCs, demonstrating that proteasomal inhibition-mediated death is not inflammatory. As MM is an inflammatory cancer, the natural microvascular environment of patients contains inflammatory cytokines. To model this, we tested the effect of exogenously added tumor necrosis factor alpha (TNF), a key inflammatory cytokine found in MM patients or supernatants from drug-treated MM1.S or PBMCs on HPMECs. Exogenously added TNF or cell-free supernatant from proteasomal inhibitor-treated immune or multiple myeloma cells combined with TNF, further compromises the cellular integrity of HPMECs when compared to drug alone conditions. Physiological levels of TNF enhance stress response in both BTZ- and CFZ-treated cells. This indicates that although proteasomal inhibition is not inflammatory, TNF present in the microvascular environment synergizes with the drugs to compromise endothelial function. Our observations provide an explanation for how microvascular damage potentially underlies tissue injury driven by Bortezomib or Carfilzomib.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1759368","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:38:57Z","timestamp":1779169137000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteasomal inhibition compromises microvascular integrity via distinct effects on non-immune endothelial cells and immune cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Prajakta","family":"Sawant","sequence":"first","affiliation":[{"name":"Doctoral Program in Biology (Molecular, Cellular & Developmental Biology), The Graduate Center, The City University of New York","place":["New York, NY, United States"]},{"name":"Department of Biological Sciences, Bronx, Lehman College, The City University of New York","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Wolf","sequence":"additional","affiliation":[{"name":"Doctoral Program in Biology (Molecular, Cellular & Developmental Biology), The Graduate Center, The City University of New York","place":["New York, NY, United States"]},{"name":"Department of Biological Sciences, Bronx, Lehman College, The City University of New York","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleena","family":"Mathew","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Bronx, Lehman College, The City University of New York","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Bensalel","sequence":"additional","affiliation":[{"name":"Doctoral Program in Biology (Molecular, Cellular & Developmental Biology), The Graduate Center, The City University of New York","place":["New York, NY, United States"]},{"name":"Department of Biological Sciences, Bronx, Lehman College, The City University of New York","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Gallego-Delgado","sequence":"additional","affiliation":[{"name":"Doctoral Program in Biology (Molecular, Cellular & Developmental Biology), The Graduate Center, The City University of New York","place":["New York, NY, United States"]},{"name":"Department of Biological Sciences, Bronx, Lehman College, The City University of New York","place":["New York, NY, United States"]},{"name":"Doctoral Program in Biochemistry, The Graduate Center, The City University of New York","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratyusha","family":"Mandal","sequence":"additional","affiliation":[{"name":"Doctoral Program in Biology (Molecular, Cellular & Developmental Biology), The Graduate Center, The City University of New York","place":["New York, NY, United States"]},{"name":"Department of Biological Sciences, Bronx, Lehman College, The City University of New York","place":["New York, NY, United States"]},{"name":"Doctoral Program in Biochemistry, The Graduate Center, The City University of New York","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2174\/156802611798281320","article-title":"Proteasome structure, function, and lessons learned from beta-lactone inhibitors","volume":"11","author":"Groll","year":"2011","journal-title":"Curr Top Med Chem"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2018.01.004","article-title":"Proteasome inhibitors: structure and function","volume":"44","author":"Nunes","year":"2017","journal-title":"Semin Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/s41408-025-01417-3","article-title":"Defining the proteome of bone marrow plasma in multiple myeloma and monoclonal gammopathy of undetermined significance","volume":"15","author":"Hsu","year":"2025","journal-title":"Blood Cancer J"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2023.103920","article-title":"An overview of multiple myeloma: a monoclonal plasma cell Malignancy's diagnosis, management, and treatment modalities","volume":"31","author":"Abduh","year":"2024","journal-title":"Saudi. 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