biostudies-literaturePerez-Stable CBLRD VAVeterans AffairsNCI NIH HHSBankhead-Coley Cancer Research Program, State of FloridaNIH HHS2442https://www.ebi.ac.uk/biostudies/studies/S-EPMC12561735biostudies-literatureUnknown13(10)<b>Background/Objective:</b> Proteotoxic stress induced by inhibitors of the ubiquitin-proteasome system has been successful in multiple myeloma but not in solid cancers such as prostate cancer. Our objective is to find a combination with proteasome inhibitors that increases apoptotic cell death in all types of prostate cancer without harming non-cancer cells. <b>Methods:</b> The effectiveness of rencofilstat, a pan-cyclophilin inhibitor, combined with the ixazomib proteasome inhibitor, was investigated in multiple prostate cancer and non-cancer cells. Inducible knockdown of stress response XBP1s and cyclophilins A/B and inducible expression of XBP1s and cyclophilin B were developed in prostate cancer to determine functional roles. <b>Results:</b> Rencofilstat + ixazomib increased apoptotiBiomedicinesCyclophilin Inhibitor Rencofilstat Combined with Proteasome Inhibitor Ixazomib Increases Proteotoxic Cell Death in Advanced Prostate Cancer Cells with Minimal Effects on Non-Cancer Cells.PMC125617351R03CA245780-22R03 CA245780I01-BX0050518BC11I01 BX005051Foster RTUre DRPerez-Stable Cde Las Pozas AWangpaichitr MfalseCyclophilin Inhibitor Rencofilstat Combined with Proteasome Inhibitor Ixazomib Increases Proteotoxic Cell Death in Advanced Prostate Cancer Cells with Minimal Effects on Non-Cancer Cells.<b>Background/Objective:</b> Proteotoxic stress induced by inhibitors of the ubiquitin-proteasome system has been successful in multiple myeloma but not in solid cancers such as prostate cancer. Our objective is to find a combination with proteasome inhibitors that increases apoptotic cell death in all types of prostate cancer without harming non-cancer cells. <b>Methods:</b> The effectiveness of rencofilstat, a pan-cyclophilin inhibitor, combined with the ixazomib proteasome inhibitor, was investigated in multiple prostate cancer and non-cancer cells. Inducible knockdown of stress response XBP1s and cyclophilins A/B and inducible expression of XBP1s and cyclophilin B were developed in prostate cancer to determine functional roles. <b>Results:</b> Rencofilstat + ixazomib increased apoptoti2025-01-01T00:00:00Z2025 Oct2026-06-04T03:07:13.383Z2026-06-04T03:05:48.491ZS-EPMC125617354115372410.3390/biomedicines13102442