{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:04:02Z","timestamp":1788998642093,"version":"build-2803163510"},"reference-count":174,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Epigenet. Epigenom."],"abstract":"<jats:p>Insulin resistance, a global metabolic crisis affecting a substantial portion of the world\u2019s 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 hypothetical cross-target repurposing strategy leveraging established \u03b1-amylase and \u03b1-glucosidase inhibitors as potential epigenetic modulators. Through systematic computational screening of 100 natural metabolic enzyme inhibitors against DNMT1 and HDAC3 crystal structures (PBD ID: 3PTA, 4A69), we identified ten dual-target candidates with binding affinities ranging from \u22128.1 to \u221210.2\u00a0kcal\/mol. Kotalanol emerged as the lead compound, demonstrating strong binding to both HDAC3 (\u22129.8\u00a0kcal\/mol) and DNMT1 (\u221210.2\u00a0kcal\/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.<\/jats:p>","DOI":"10.3389\/freae.2025.1691949","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T06:24:01Z","timestamp":1761805441000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Epigenetic repurposing of carbohydrate metabolic inhibitors for insulin resistance: targeting DNMT1 and HDAC3 for \u03b2-cell restoration"],"prefix":"10.3389","volume":"3","author":[{"given":"Muhammad Javid","family":"Iqbal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis A.","family":"Salazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1007\/s00580-015-2119-7","article-title":"Antioxidant and antidiabetic effects of gallic and protocatechuic acids: a structure\u2013function perspective","volume":"24","author":"Adefegha","year":"2015","journal-title":"Comp. 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