Fig. 6: DLD targeting therapy in myeloma in vivo.

A Bioluminescence image of four groups of mice (Blank, BTZ, CPI-613, and BTZ + CPI-613) on the 11th, 18th, and 32nd days. The results showed that the BTZ combined with the CPI-613 treatment group had the best therapeutic effect (p < 0.05). B The kappa light chain detection results on the peripheral blood of the four groups of mice on the 11th, 18th, and 32nd days showed that the BTZ combined with the CPI-613 treatment group had lower κ light chain content than the BTZ treatment group (p < 0.05). C The survival curves from four groups of mice showed that the BTZ combined with the CPI-613 treatment group had the longest survival time (p < 0.05). D The IHC staining results of leg bone pathological sections from four groups of mice showed that the BTZ combined with the CPI-613 group had the highest expression of cleaved caspase 3 (brown color showed positive staining for cleaved caspase 3, p < 0.05). E The results showed that there were no significant differences in white blood cells (WBC), hemoglobin (HGB), platelets (PLT), alanine aminotransferase (ALT), direct bilirubin (D-BIL), and creatinine (CREA) between the 7th day from each group of mice (p > 0.05). F The HE staining results of organ pathology sections of mice in each group on the 7th day after treatment showed that no significant pathological changes were found in the heart, liver, lungs, and kidney issues. G Pattern diagram of DLD regulating PIs resistance in MM. After the interaction between BTZ and DLD, the activity of its constituent enzyme PDH and the content of its catalytic product NADH both decreased, leading to a decrease in the binding of NADH to the 19S proteasome subunit PSMC1, resulting in abnormal assembly of proteasomes and further inhibition of proteasome activity. The decrease in proteasome activity activated the UPR signaling pathway, inducing cell apoptosis.