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Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma by stabilizing IRF4 via NAT10-mediated acetylation

ABSTRACT:

Multiple myeloma (MM) remains an incurable hematologic malignancy despite advances in treatment. While obesity is a well-established risk factor, the underlying metabolic mechanisms by which adipocytes contribute to disease progression remain elusive. Here, we uncover a critical metabolic crosstalk between adipocytes and MM cells that promotes MM cell survival under glucose deprivation. We show that glucose restriction activates AMPK, leading to subcellular relocalization of HSP90 and disruption of its protective interaction with the oncoprotein IRF4, thereby rendering IRF4 susceptible to TRIM21-mediated ubiquitination and proteasomal degradation. Paradoxically, the same metabolic stress stimulates adipocytes to upregulate ketogenesis and produce β-hydroxybutyrate (β-OHB). MM cells utilize β-OHB via OXCT1-mediated ketolysis, fueling NAT10-dependent acetylation of IRF4 at K87. This acetylation event restores IRF4-HSP90 binding, thereby shielding IRF4 from degradation and sustaining tumor cell survival. Genetic ablation of Hmgcs2, the rate-limiting ketogenic enzyme, in adipocytes abrogates this protective effect. Importantly, combining an AMPK activator (metformin) with either an OXCT1 inhibitor (pimozide) or a NAT10 inhibitor (remodelin) results in potent synergistic antitumor activity in vivo. Our study thus positions β-OHB as a critical metabolic adaptor that empowers myeloma cells to circumvent glucose metabolic stress and highlights a promising combination therapeutic strategy that exploits the vulnerability arising from competing metabolic dependencies.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14445 | MetaboLights | 2026-05-07

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14445_LC-MS_negative_reverse-phase.txt	Txt
	a_MTBLS14445_LC-MS_positive_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14445_LC-MS_negative_reverse-phase_v2_maf.tsv	Tabular
	m_MTBLS14445_LC-MS_positive_reverse-phase_v2_maf.tsv	Tabular

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Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma by stabilizing IRF4 via NAT10-mediated acetylation

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