ArticleMolecular medicine (Cambridge, Mass.)2025
O-GlcNAcylation with ubiquitination stabilizes METTL3 to promoting HMGB1 degradation to inhibit ferroptosis and enhance gemcitabine resistance in pancreatic cancer.
Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Distinct O-Linked Glycosylation Systems in Signaling and Immune Regulation.International journal of molecular sciences · 2026Review
- The RNA methylation modification as an immunometabolic regulatory hub in pancreatic cancer: from mechanistic insights to clinical translation perspectives.Molecular cancer · 2026Review
- HMGB1 as Double-Edged Regulator of Cancer Therapy: Mechanistic Roles in Chemotherapy Resistance and Immunotherapy Response.OncoTargets and therapy · 2026Review
- O-GlcNAcylation at the tumor-immune interface: a metabolic post-translational code driving immune evasion and therapy resistance in cancer.Frontiers in immunology · 2026Review
- Mechanism and therapeutic prospects of ferroptosis regulation through m6A in cancer.Frontiers in cell and developmental biology · 2026Review
- O-GlcNAcylation in novel regulated cell death: ferroptosis, pyroptosis, and necroptosis.Cell death discovery · 2025Review
- O‑GlcNAcylation: The crosstalk between infection immunity and autophagy in sepsis (Review).Molecular medicine reports · 2025Review
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Authors and funding
11 authors.
Funding
Abstract
backgroundPancreatic cancer is highly lethal, and METTL3 plays a crucial role in the regulation of m6A. However, the therapeutic potential of METTL3 in pancreatic cancer is unclear.
methodsBy means of functional gain and loss experiments, the relationship between METTL3 and gemcitabine resistance as well as ferroptosis was explored. The target genes of METTL3 were screened, and the influence of O-GlcNAcylation on the stability and ubiquitination modification of METTL3 was dissected.
resultsWe found that METTL3 is highly expressed in pancreatic cancer and regulates ferroptosis and gemcitabine resistance by promoting the degradation of HMGB1 in an m6A-YTHDF2-dependent manner. O-GlcNAcylation modulates the METTL3’s stability. The interaction between the deubiquitinase EIF3H and METTL3 is influenced by O-GlcNAcylation.
conclusionMETTL3 affects pancreatic cancer progression by promoting degradation of HMGB1. The O-GlcNAcylation of METTL3 not only stabilizes METTL3 but also augments EIF3H-mediated deubiquitination. These findings uncover potential mechanisms underlying gemcitabine resistance in pancreatic cancer and offer potential therapeutic strategies for the treatment of this disease.
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