ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
Pharmacological Dissection Identifies Retatrutide Overcomes the Therapeutic Barrier of Obese TNBC Treatments through Suppressing the Interplay between Glycosylation and Ubiquitylation of YAP.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- RIBOTAC-mediated degradation of hsa-microRNA-301a-3p suppresses TNBC bone metastasis.Science advances · 2026Article
- GLP-1 receptor agonist use and overall survival among women with type 2 diabetes and breast cancer: a retrospective cohort study.The oncologist · 2026Article
- Serum Starvation Promotes the Proteolysis of OGT by Activating AMPK and the CUL1/SKP1/SKP2 E3 Ubiquitin Ligase in 3T3-L1 Cells.Biomolecules & therapeutics · 2026Article
- GFPT2 upregulation predicts poor prognosis and is associated with TGF-β/Smad activation in lung adenocarcinoma.Discover oncology · 2026Article
- F2R and MXRA5: the metabolic obesity-derived biomarkers for immunosuppression and poor survival in triple-negative breast cancer.Discover oncology · 2026Article
- eIF3 musketeers: loyal in health, rogue in disease, and redeemed by therapeutic targeting.The EMBO journal · 2026Review
- YAP1 in control: how RNA networks and protein modifications shape its function and therapeutic targetability.Molecular cancer · 2026Review
- Obesity-induced metabolic reprogramming of the tumor immune microenvironment: mechanisms, spatial niches, and immunotherapy response.Frontiers in immunology · 2026Review
- NEDD4 promotes reactive astrogliosis by enhancing K63-linked ubiquitination and inhibiting chaperone-mediated autophagy degradation of YAP1.International journal of biological sciences · 2026Article
- Reducing OGT and O-GlcNAcylation enhance the anticancer effects of oxaliplatin in SW620 metastatic colorectal cancer cells.PloS one · 2026Article
- Contractile effects of retatrutide in isolated mouse atrial preparations.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Posttranslational modifications of YAP/TAZ: molecular mechanisms and therapeutic opportunities.Cellular & molecular biology letters · 2025Review
- GLP-1 receptor agonists in the context of cancer: the road ahead.American journal of physiology. Cell physiology · 2025 · on this mapReview
- Pharmacological Dissection Identifies Retatrutide Overcomes the Therapeutic Barrier of Obese TNBC Treatments through Suppressing the Interplay between Glycosylation and Ubiquitylation of YAP.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Ferroptosis and pyroptosis in diabetes mellitus: emerging therapeutic potential of GLP-1 receptor agonists.Frontiers in clinical diabetes and healthcare · 2025Review
Corrections and comments
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Authors and funding
10 authors.
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Abstract
Triple-negative breast cancer (TNBC) in obese patients remains challenging. Recent studies have linked obesity to an increased risk of TNBC and malignancies. Through multiomic analysis and experimental validation, a dysfunctional Eukaryotic Translation Initiation Factor 3 Subunit H (EIF3H)/Yes-associated protein (YAP) proteolytic axis is identified as a pivotal junction mediating the interplay between cancer-associated adipocytes and the response to anti-cancer drugs in TNBC. Mechanistically, cancer-associated adipocytes drive metabolic reprogramming resulting in an upregulated hexosamine biosynthetic pathway (HBP). This aberrant upregulation of HBP promotes YAP O-GlcNAcylation and the subsequent recruitment of EIF3H deubiquitinase, which stabilizes YAP, thus promoting tumor growth and chemotherapy resistance. It is found that Retatrutide, an anti-obesity agent, inhibits HBP and YAP O-GlcNAcylation leading to increased YAP degradation through the deprivation of EIF3H-mediated deubiquitylation of YAP. In preclinical models of obese TNBC, Retatrutide downregulates HBP, decreases YAP protein levels, and consequently decreases tumor size and enhances chemotherapy efficacy. This effect is particularly pronounced in obese mice bearing TNBC tumors. Overall, these findings reveal a critical interplay between adipocyte-mediated metabolic reprogramming and EIF3H-mediated YAP proteolytic control, offering promising therapeutic strategies to mitigate the adverse effects of obesity on TNBC progression.
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Registered trials
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.