ArticleExperimental & molecular medicine2022
Homocysteine-targeting compounds as a new treatment strategy for diabetic wounds via inhibition of the histone methyltransferase SET7/9.
Article in Experimental & molecular medicine, 2022. 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, 29 citations in OpenAlex.
- Direct Targeting of Gene Regulators by Iridium(III) and Rhodium(III) Complexes.Accounts of chemical research · 2025Article
- Angiogenesis during diabetic wound repair: from mechanism to therapy opportunity.Burns & trauma · 2025Review
- Current research progress on the use of traditional Chinese medicine in the treatment of diabetic foot ulcers.Frontiers in endocrinology · 2025Review
- Wound management, healing, and early prosthetic rehabilitation: Part 3 - A scoping review of chemical biomarkers.Canadian prosthetics & orthotics journal · 2025Review
- Lysine and arginine methylation of transcription factors.Cellular and molecular life sciences : CMLS · 2024Review
- Roles of Lysine Methylation in Glucose and Lipid Metabolism: Functions, Regulatory Mechanisms, and Therapeutic Implications.Biomolecules · 2024Review
- Epigenetic mechanism of SET7/9-mediated histone methylation modification in high glucose-induced ferroptosis in retinal pigment epithelial cells.Journal of bioenergetics and biomembranes · 2024Article
- Review
- Wound management, healing, and early prosthetic rehabilitation: Part 2 - A scoping review of physical biomarkers.Canadian prosthetics & orthotics journal · 2024Review
- Histone modifications and their roles in macrophage-mediated inflammation: a new target for diabetic wound healing.Frontiers in immunology · 2024Review
- Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing definitions.Canadian prosthetics & orthotics journal · 2024Review
- Tumor-suppressive functions of protein lysine methyltransferases.Experimental & molecular medicine · 2023Review
- Development of a dual targeting scaffold of SET7/MLL inhibitor for castration-resistant prostate cancer treatment.Genes & diseases · 2023Article
- Discovery and evaluation of active compounds from Xuanfei Baidu formula against COVID-19 via SARS-CoV-2 MChinese medicine · 2023Article
- A novel family of small molecule HIF-1 alpha stabilizers for the treatment of diabetic wounds; an integratedRSC advances · 2022Article
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In hypoxia and hyperglycemia, SET7/9 plays an important role in controlling HIF-1α methylation and regulating the transcription of HIF-1α target genes, which are responsible for angiogenesis and wound healing. Here, we report the Ir(III) complex Set7_1a bearing acetonitrile (ACN) ligands as a SET7/9 methyltransferase inhibitor and HIF-1α stabilizer. Interestingly, Set7_1a could engage SET7/9 and strongly inhibit SET7/9 activity, especially after preincubation with homocysteine (Hcy), which is elevated in diabetes. We hypothesize that Set7_1a exchanges ACN subunits for Hcy to disrupt the interaction between SET7/9 and SAM/SAH, which are structurally related to Hcy. Inhibition of SET7/9 methyltransferase activity by Set7_1a led to reduced HIF-1α methylation at the lysine 32 residue, causing increased HIF-1α level and recruitment of HIF-1α target genes that promote angiogenesis, such as VEGF, GLUT1, and EPO, in hypoxia and hyperglycemia. Significantly, Set7_1a improved wound healing in a type 2 diabetic mouse model by activating HIF-1α signaling and downstream proangiogenic factors. To our knowledge, this is the first Hcy-targeting iridium compound shown to be a SET7/9 antagonist that can accelerate diabetic wound healing. More importantly, this study opens a therapeutic avenue for the treatment of diabetic wounds by the inhibition of SET7/9 lysine methyltransferase activity.
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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.