REVIEW article
Front. Epigenet. Epigenom.
Sec. Epigenetics and Metabolism
Volume 3 - 2025 | doi: 10.3389/freae.2025.1691949
This article is part of the Research TopicMetabolic and Nutritional Influences on Epigenetic LandscapesView all articles
Epigenetic Repurposing of Carbohydrate Metabolic Inhibitors for Insulin Resistance: Targeting DNMT1 and HDAC3 for β-Cell Restoration
Provisionally accepted
- 1Programa de Doctorado en Ciencias de Recursos Naturales, Universidad de La Frontera, Temuco, Chile
- 2Universidad de la Frontera Facultad de Medicina, Temuco, Chile
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Insulin resistance, a global metabolic crisis affecting a substantial portion of the world's population, involves complex metabolic-epigenetic crosstalk that current therapies fail to address. DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3) progressively silence insulin signaling genes, creating a self-perpetuating cycle of metabolic dysfunction. We present a novel cross-target repurposing strategy leveraging established α-amylase and α-glucosidase inhibitors as potential epigenetic modulators. Through systematic computational screening of 100 natural metabolic enzyme inhibitors against DNMT1 and HDAC3 crystal structures (PDB: 3PTA, 4A69), we identified ten dual-target candidates with binding affinities ranging from -8.1 to -10.2 kcal/mol. Kotalanol emerged as the lead compound, demonstrating exceptional binding to both HDAC3 (-9.8 kcal/mol) and DNMT1 (-10.2 kcal/mol). Molecular docking revealed that polyphenolic metabolic inhibitors share structural features enabling interaction with epigenetic enzyme active sites, particularly zinc-binding motifs and aromatic pockets. ADMET profiling confirmed favorable pharmacokinetic properties for the top candidates. Clinically validated compounds including berberine, curcumin, and EGCG provide proof-of-concept for dual metabolic-epigenetic activity. This repurposing approach offers significant advantages: utilizing compounds with established safety profiles, addressing multiple pathogenic mechanisms simultaneously, and accelerating therapeutic development. By targeting both immediate glucose control and long-term epigenetic preservation, these dual-action compounds could transform diabetes management from symptomatic treatment to mechanistic intervention, potentially reversing insulin resistance progression rather than merely managing hyperglycemia.
Keywords: Insulin Resistance, epigenetics, Dnmt1, HDAC3, metabolic enzyme inhibitors, cross-target therapeutics, Naturalproducts, Computational screening
Received: 24 Aug 2025; Accepted: 02 Oct 2025.
Copyright: © 2025 Iqbal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Muhammad Javid Iqbal, m.iqbal01@ufromail.cl
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