Passero FC, et al. - Since ixazomib activity and transcriptomic analyses earlier discovered in T cell (TCL) and Hodgkin (HL) lymphoma models predicted synergistic activity for histone deacetylase (HDAC) inhibitory combination, researchers focused on the mechanistic basis for ixazomib combination with belinostat (the HDAC inhibitor) in HL and TCL cells lines (ixazomib-sensitive/resistant clones) and primary tumour cells. Abrogation of NFE2L2, proteasome gene expression and functional recovery by ixazomib + belinostat combination was observed using transcriptomic and proteasomal activity evaluation of ixazomib, belinostat, or ixazomib + belinostat treated cells; this led to synergistic drug activity in ixazomib-sensitive and -resistant cell lines and primary cells. According to the findings, the synergistic activity of ixazomib + belinostat was found to be mediated through inhibition NFE2L2-dependent proteasomal recovery and extended proteasomal inhibition ending in increased cell death.