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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Multiple Myeloma

SUBMITTER: 瑞李

LAB HEAD: Rui Li

PROVIDER: PXD076575 | Pride | 2026-05-07

REPOSITORIES: Pride

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			Action	DRS
	IRF4-GFP.raw	Raw
	checksum.txt	Txt
	md5sum.txt	Txt
	uniprot-Reference-Homosapiens.fasta	Fasta

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Similar Datasets

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

Project description: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.

2026-05-07 | PXD070988 | Pride

Adipocyte-Derived β-Hydroxybutyrate Confers Metabolic Stress Resistance in Multiple Myeloma-2

2026-05-07 | PXD065472 | Pride

Adipocytes-derived β-hydroxybutyrate confers the resistance of myeloma cells to metabolic stress

Project description:Albeit being recognized as one of the major mesenchymal cells and a dangerous accomplice in myeloma, the roles of adipocytes in different stages of myeloma pathogenesis remain elusive. Here we showed that glucose metabolic stress impairs protein stability of interferon regulatory factor 4 (IRF4), an oncoprotein essential for myeloma cell survival, while adipocytes-derived β-hydroxybutyrate (β-OHB) preserves IRF4 stability and cell survival. Mechanistically, glucose deficiency activates the AMP-activated protein kinase (AMPK) to disrupt the interaction of IRF4 with heat shock protein 90 (HSP90), enabling the E3 ligase TRIM21-mediated IRF4 ubiquitination degradation. The presence of β-OHB drives 3-oxoacid CoA-transferase 1 (OXCT1)-mediated ketolysis and facilitates N-acetyltransferase 10 (NAT10)-mediated IRF4 acetylation at lysine 87, which restores IRF4’s interaction with HSP90 and precludes TRIM21-mediated IRF4 degradation. Notably, targeting OXCT1 or NAT10 to interfere with β-OHB utilization displays a synergistic anti-myeloma effect in combination with AMPK activator both in vitro and in vivo. Our study thus positions adipocytes-derived β-OHB as a pivotal contributor that enables myeloma cells to overcome glucose metabolic stress and suggests viable therapeutic targets to be exploited for multiple myeloma treatment.

2025-06-23 | GSE290392 | GEO

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

Project description:<p> 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.</p>

2026-05-07 | MTBLS14445 | MetaboLights

TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting pro-survival autophagy

Project description:Bortezomib (bort) is an effective therapeutic agent for multiple myeloma (MM) patients; however, the majority of patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif-containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, while TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phospho-proteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated pro-survival autophagy. Our results provided that TRIM21 KD MM cell lines induced pro-survival autophagy after bort treatment, and suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of ATG5 restored bort sensitivity. Indeed, autophagy-related gene 5 (ATG5) expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the anti-myeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approaches.

2023-10-24 | PXD042004 | Pride

Fasting enriched metabolic enhancers associate with histone lysine 9 ß-hydroxybutyrylation

Project description:β-hydroxybutyrate (β-OHB) is an essential metabolic energy source during fasting and functions as a chromatin regulator by lysine β-hydroxybutyrylation (Kbhb) modification of the core histones H3 and H4. We report that Kbhb on histone H3 (H3K9bhb) is enriched at proximal promoters of critical gene subsets associated with lipolytic and ketogenic metabolic pathways in small intestine (SI) crypts during fasting. Similar Kbhb enrichment is observed in Lgr5+ stem cell-enriched epithelial spheroids treated with β-OHB in vitro. Combinatorial chromatin state analysis reveals that H3K9bhb is associated with active chromatin states and that fasting enriches for an H3K9bhb-H3K27ac signature at active metabolic gene promoters and distal enhancer elements. Intestinal knockout of Hmgcs2 results in marked loss of H3K9bhb-associated loci, suggesting that local production of β-OHB is responsible for chromatin reprogramming within the SI crypt. We conclude that modulation of H3K9bhb in SI crypts is a key gene regulatory event in response to fasting.

2021-11-23 | GSE122896 | GEO

EZH2 inhibition overcomes immunomodulatory drug (IMiD) resistance in multiple myeloma cell lines in a CRBN pathway dependent manner

Project description:Immunomodulatory agents (IMiDs) and the next-generation Cereblon (CRBN) E3 ligase modulators (CeLMoDs), targeting the Ikaros/Aiolos-IRF4-MYC axis, are effective therapies for multiple myeloma (MM) across all stages of disease. Resistance to treatment can be acquired following exposure, but a subset of patients have primary resistance, with both states necessitating the development of alternative treatment strategies. Enhancer of zeste homolog 2 (EZH2) has been shown to have increased expression at myeloma relapse and higher expression is associated with a shorter progression free survival from diagnosis. EZH2 inhibitors have been studied as a single agent in myeloma and in combination treatments to overcome drug resistant in other malignancies. In this study KMS11 and RPMI-8226 myeloma cell lines are used as models of primary IMID resistance, with persistent Interferon regulatory factor 4 (IRF4) expression after IMiDs/CeLMoDs exposure without loss of cell viability. The combination of Tazemetostat, an FDA-approved EZH2 inhibitor, with IMiDs/CeLMoDs significantly reduces IRF4 expression, induces apoptosis, and leads to synergistic cell death in these resistant cell lines. Further investigations reveal that the synergistic effect of EZH2 inhibition is specific to IMiDs/CeLMoDs, is CRBN-dependent and rescued by IRF4 over-expression. Mechanistically, Tazemetostat appears to reduce Ikaros binding to the IRF4 promoter, explaining how the combination with IMiDs/CeLMoDs which also have this effect can reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.

2026-03-19 | PXD057933 | Pride

Homo sapiens

Project description:IRF4 and Myeloma

| PRJNA102397 | ENA

Myeloma IRF4 target genes - Agilent

Project description:The goal of this gene expression study was to identify genes whose expression depends on the transription factor IRF4 by knocking down it's expression using shRNA in two IRF4+ myeloma cell lines. Keywords: time series design Two myeloma lines were analyzed over a time course of IRF4-targeted shRNA induction. There are 3 time courses: two using KMS12 (biological replicates) and one with SKMM1. Within each time course there are technical replicates.

2010-05-26 | E-GEOD-9067 | biostudies-arrayexpress

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Project description:SjÃ¶gren's syndrome is an autoimmune disease manifesting primarily as dryness of eyes and mouth. In this study, we compared gene expression in PBMCs between age- and gender-matched patients with SjÃ¶gren's syndrome (diagnosed by ACR criteria) and healthy controls. Cells were collected in heparinized tubes and PBMCs were prepared using Ficoll. Eleven patients with SjÃ¶gren's syndrome and 16 healthy controls were analyzed for expression of TRIM21, IRF1, IRF2, IRF4 and IRF8.

2013-09-05 | E-GEOD-48378 | biostudies-arrayexpress

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