Adipocyte-Derived β-Hydroxybutyrate Confers Metabolic Stress Resistance in Multiple Myeloma

Despite being recognized as a major mesenchymal cell type and a key accomplice in myeloma progression, the precise roles of adipocytes in distinct stages of myeloma pathogenesis remain elusive. Here, we elucidate a critical role of adipocyte-derived β-hydroxybutyrate (β-OHB) in enabling myeloma cells to overcome glucose metabolic stress by sustaining the stability of interferon regulatory factor 4 (IRF4), a master oncoprotein essential for myeloma survival. Under glucose deprivation conditions, AMP-activated protein kinase (AMPK) activation disrupts the IRF4-heat shock protein 90 (HSP90) interaction, enabling the E3 ligase TRIM21-mediated IRF4 ubiquitination and proteasomal degradation. Adipocytes-secreted β-OHB counteracts this process by fueling 3-oxoacid CoA-transferase 1 (OXCT1)-dependent ketolysis and activating N-acetyltransferase 10 (NAT10) to acetylate IRF4 at lysine 87, thereby restoring IRF4-HSP90 binding and blocking TRIM21-mediated IRF4 degradation. Notably, pharmacological inhibition of OXCT1 or NAT10, combined with AMPK activator, synergistically suppresses myeloma growth in vitro and in vivo . Our study thus positions adipocytes-derived β-OHB as a critical metabolic adaptor that empowers myeloma cells to circumvent glucose metabolic stress and highlights a promising therapeutic avenue for targeting metabolic vulnerabilities in multiple myeloma.