SRP436173 PRJNA967646 hRpn13 binds epigenetic transcriptional regulators HDAC8 and PADI4 with its loss causing a reconfigured proteome and transcriptome hRpn13 is an established proteasome substrate receptor that also exists off proteasomes. We demonstrate that its deletion by gene-editing leads to correlated proteomic and transcriptomic changes and that these effects are cell type-specific. The hRpn13 Pru region, which binds proteasomes and ubiquitin, directly interacts with two regulators of protein expression; namely, the histone deacetylase HDAC8, which we find to be inhibited by hRpn13 in a catalytic assay and to interact with hRpn13 off proteasomes, and bone marrow-specific protein arginine deimidase PADI4, which is depleted from multiple myeloma cells by either hRpn13 loss or proteasome inhibition. The NF-kB p105 precursor protein is partially proteolyzed by the proteasome to yield transcription activator p50; we find hRpn13 deletion or loss by PROTAC targeting to reduce p50 levels and that loss of hRpn13 or NF-kB inhibition reduces PADI4 and HDAC8 protein abundance, with their mRNA depleted by proteasome inhibition. Altogether, we discover a multi-layered regulatory network that connects hRpn13 to NF-kB activity and epigenetic regulators of arginine deimination and histone deacetylation.