Evidence map›Paper›PMID 41376547›Full record

ArticleHaematologica2026

Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.

Shanna M Hogeling, Dominique Sternadt, Nikita La Rose, Marjan Geugien, Diego Pereira-Martins, Fiona A J Van den Heuvel, Anna Kuchnio, Christine E Pietsch, Ulrike Philippar, Gerwin Huls and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Haematologica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Shanna M HogelingDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen.
Dominique SternadtDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen.
Nikita La RoseDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen.
Marjan GeugienDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen.
Diego Pereira-MartinsDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen.
Fiona A J Van den HeuvelDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen.
Anna KuchnioDiscovery Oncology, Janssen Research and Development, Beerse, BE.
Christine E PietschDiscovery Oncology, Janssen Research and Development, Spring House, PA.
Ulrike PhilipparDiscovery Oncology, Janssen Research and Development, Beerse, BE.
Gerwin HulsDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen.
Jan Jacob SchuringaDepartment of Hematology, University Medical Center Groningen, University of Groningen, Groningen. j.j.schuringa@umcg.nl.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Acute myeloid leukemia (AML) remains difficult to cure, in part related to strong genetic and functional heterogeneity between and within individual patients. Metabolic reprogramming is emerging as an important feature of AML cells, allowing exploration of alternative treatment strategies. Here, we describe a novel DHODH inhibitor, JNJ-74856665, that showed strong efficacy in a subset of AML samples. In a multi-omics approach, by combining label-free quantitative proteome data with drug sensitivity data in bone marrow stromal co-cultures in a large cohort of primary AML patient samples we identified that sensitivity to DHODH inhibition (DHODHi) is linked to cholesterol and lipid metabolism. DHODHi resulted in an accumulation of cholesterol, mitochondrial reactive oxygen species (ROS) and lipid peroxidation. LC-MS/ MS-based lipidomics studies revealed that DHODHi resulted in a strong increase in polyunsaturated fatty acids and triglycerides, which are the primary lipid species stored in lipid droplets (LD). We hypothesized that this might be the consequence of increased ROS and lipid peroxidation levels, prompting the cell to detoxify such toxic lipid species by storing them in LD. Indeed, we could observe a marked increase in LD formation upon DHODHi. The transcriptional regulator SREBF2, known to control cholesterol and lipid metabolism, was up-regulated in DHODHi sensitive AML, and a strong synergy was observed between the combination of both DHODHi and the SREBP inhibitor dipyridamole. Our data indicate that it would be interesting to further explore combined DHODH and SREBP inhibition as a therapeutic target option in AML.

Indexed as

CholesterolEnzyme InhibitorsLeukemia, Myeloid, AcuteLipid MetabolismOxidoreductases Acting on CH-CH Group DonorsSterol Regulatory Element Binding Protein 1Sterol Regulatory Element Binding Protein 2Dihydroorotate DehydrogenaseDrug SynergismHumansReactive Oxygen SpeciesCholesterolDihydroorotate DehydrogenaseEnzyme InhibitorsOxidoreductases Acting on CH-CH Group DonorsReactive Oxygen SpeciesSterol Regulatory Element Binding Protein 1Sterol Regulatory Element Binding Protein 2

Identifiers

PMID41376547
PMCPMC13317884

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.