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

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: Li Rui

PROVIDER: PXD065472 | Pride | 2026-05-07

REPOSITORIES: Pride

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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

2026-05-07 | PXD076575 | 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

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

Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK

Project description:Obesity is an epidemic affecting 13% of the global population and increasing the risk of many chronic diseases. However, only several drugs are licensed for pharmacological intervention for the treatment of obesity. As a master regulator of metabolism, the therapeutic potential of AMPK is widely recognized and aggressively pursued for the treatment of metabolic diseases. We found that elaiophylin (Ela) rapidly activates AMPK in a panel of cancer cell lines, as well as primary hepatocytes and adipocytes. Meanwhile, Ela inhibits the mTORC1 complex, turning on catabolism and turning off anabolism together with AMPK. In vitro and in vivo studies showed that Ela does not activate AMPK directly; instead, it increases cellular AMP/ATP and ADP/ATP ratios, leading to AMPK phosphorylation in a LKB1-dependent manner. AMPK activation induced by Ela caused changes in diverse metabolic genes, thereby promoting glucose consumption and fatty acid oxidation. Importantly, Ela activates AMPK in mouse liver and adipose tissue. As a consequence, it reduces body weight and blood glucose levels and improves glucose and insulin tolerance in both ob/ob and high fat diet-induced obese mouse models. Our study has identified a novel AMPK activator as a candidate drug for the treatment of obesity and its associated chronic diseases.

2021-10-27 | GSE182566 | GEO

Secreted Protein Acidic and Rich in Cysteine Improves Glucose Tolerance via AMP-activated Protein Kinase Activation

Project description:Metabolic dysfunction of skeletal muscle is often prevalent at an early stage in the development of several non-communicable diseases. Here, we investigated the effect of a myokine, secreted protein acidic and rich in cysteine (SPARC), on glucose tolerance in human and mouse skeletal muscles. SPARC knockout mice showed marked decreases in parameters for whole-body glucose metabolism, along with reduced phosphorylation of AMPK and Akt in skeletal muscle tissues compared with wild-type mice. Furthermore, mice injected with SPARC showed improved glucose tolerance concomitant with AMPK activation. Exogenous SPARC treatment accelerated glucose uptake in muscle tissues isolated from wild-type mice but not from AMPKγ3 knockout mice. In muscle cells, SPARC increased glucose uptake concomitant with AMPK activation, mediated by a calcium-dependent signal. Chronic treatment of SPARC restored metabolic functions in diet-induced obese mice. These findings suggest that SPARC improves glucose metabolism via AMPK activation in skeletal muscle, providing mechanistic insights on exercise-induced metabolic benefits and physical inactivity-induced glucose intolerance.

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

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

| PRJNA1227882 | ENA

Baicalin alleviates lipid accumulation in adipocytes via inducing metabolic reprogramming and targeting Adenosine A1 receptor

Project description:Excessive lipid accumulation can lead to obesity, metabolic-associated fatty liver disease, and type 2 diabetes. However, there are currently few drugs that could effectively and safely inhibit the accumulation of intracellular lipid. In this study, we observed that baicalin significantly altered cellular respiration by reducing mitochondrial oxygen consumption while enhancing glycolytic flux, accompanied by increased phosphorylation of AMPK and ACC, suggesting an adaptation to altered energy availability. Baicalin effectively reduced lipid droplet formation and intracellular triglyceride levels in adipocytes, as marked by downregulating genes and proteins associated with lipid storage, including Cd36, Fabp4, and FASN. Transcriptomic analysis identified 2,150 differentially expressed genes in baicalin-treated adipocytes, with significant enrichment in metabolic pathways such as glycolysis, gluconeogenesis, and lipid metabolism. Further analysis revealed that baicalin upregulated glycolytic and fatty acid β-oxidation (FAO) pathways while downregulating pyruvate dehydrogenase, inducing a shift toward glycolysis and FAO for energy production. Molecular docking analysis revealed that adenosine A1 receptor (ADORA1) was the target of baicalin, which inhibited the maturation of sterol regulatory element binding protein 1 (SREBP1) and finally alleviated lipid deposition. These results demonstrate that baicalin induces metabolic reprogramming of adipocytes by inhibiting glucose aerobic metabolism while enhancing anaerobic glycolysis and FAO. Meanwhile, baicalin targets ADORA1, which subsequently influences the processing of SREBP1 and downregulates lipid biosynthesis, positioning baicalin as a potential therapeutic agent against obesity and related metabolic disorders.

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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

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