ArticleProceedings of the National Academy of Sciences of the United States of America2022
Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 27 citations in OpenAlex.
- A Selective Cullin 3 RING E3 Ligase Inhibitor Attenuates Hyperglycemia via Dual Insulin Sensitizing and Insulinotropic Action.Diabetes · 2026Article
- E3 ligase FBXO2-mediated protein stability of insulin receptor regulates adipogenesis and metabolic health in obesity.Cell death & disease · 2026Article
- Role of neddylation in diabetes metabolism: potential therapeutic target.Journal of diabetes and metabolic disorders · 2026Review
- Metabolic dysfunction-associated steatotic liver disease: pathogenesis and novel treatment options.Molecular biomedicine · 2026Review
- The inner nuclear membrane protein SUN1 regulates cullin-3 neddylation to maintain insulin signaling.bioRxiv : the preprint server for biology · 2026Article
- DCUN1D5 promotes the proliferation and migration of colorectal cancer tumors in vitro and in vivo.Cancer cell international · 2026Article
- Emerging Roles of Post-Translational Modifications in Metabolic Homeostasis and Type 2 Diabetes.International journal of molecular sciences · 2025Review
- Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Ubiquitination and ubiquitin-like modifications in metabolic dysfunction-associated steatotic liver disease: mechanisms and implications.BMB reports · 2025Review
- The insulin signalling network.Nature metabolism · 2025Review
- Deciphering the roles of neddylation modification in hepatocellular carcinoma: Molecular mechanisms and targeted therapeutics.Genes & diseases · 2025Review
- The ubiquitin-proteasome system: A potential target for the MASLD.Acta pharmaceutica Sinica. B · 2025Review
- Therapeutic Potential ofFood science & nutrition · 2025Article
- Neddylation steers the fate of cellular receptors.Experimental & molecular medicine · 2024Review
- Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Neddylation suppression by a macrophage membrane-coated nanoparticle promotes dual immunomodulatory repair of diabetic wounds.Bioactive materials · 2024Article
- Integrated analysis reveals the regulatory mechanism of the neddylation inhibitor MLN4924 on the metabolic dysregulation in rabbit granulosa cells.BMC genomics · 2024Article
- Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila.Nature communications · 2024Article
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Authors and funding
8 authors at 2 institutions in 1 country.
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Abstract
Hepatic insulin resistance is a hallmark feature of nonalcoholic fatty liver disease and type-2 diabetes and significantly contributes to systemic insulin resistance. Abnormal activation of nutrient and stress-sensing kinases leads to serine/threonine phosphorylation of insulin receptor substrate (IRS) and subsequent IRS proteasome degradation, which is a key underlying cause of hepatic insulin resistance. Recently, members of the cullin-RING E3 ligases (CRLs) have emerged as mediators of IRS protein turnover, but the pathophysiological roles and therapeutic implications of this cellular signaling regulation is largely unknown. CRLs are activated upon cullin neddylation, a process of covalent conjugation of a ubiquitin-like protein called Nedd8 to a cullin scaffold. Here, we report that pharmacological inhibition of cullin neddylation by MLN4924 (Pevonedistat) rapidly decreases hepatic glucose production and attenuates hyperglycemia in mice. Mechanistically, neddylation inhibition delays CRL-mediated IRS protein turnover to prolong insulin action in hepatocytes. In vitro knockdown of either cullin 1 or cullin 3, but not other cullin members, attenuates insulin-induced IRS protein degradation and enhances cellular insulin signaling activation. In contrast, in vivo knockdown of liver cullin 3, but not cullin 1, stabilizes hepatic IRS and decreases blood glucose, which recapitulates the effect of MLN4924 treatment. In summary, these findings suggest that pharmacological inhibition of cullin neddylation represents a therapeutic approach for improving hepatic insulin signaling and lowering blood glucose.
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