{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:26:06Z","timestamp":1785432366823,"version":"3.56.0"},"reference-count":118,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Science and Technology","award":["DST\/2022\/1012"],"award-info":[{"award-number":["DST\/2022\/1012"]}]},{"award":["DST\/2022\/1012"],"award-info":[{"award-number":["DST\/2022\/1012"]}],"id":[{"id":"https:\/\/ror.org\/0101xrq71","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Manipal University Jaipur","award":["EF\/2025-26\/QE-04-15"],"award-info":[{"award-number":["EF\/2025-26\/QE-04-15"]}]},{"award":["EF\/2025-26\/QE-04-15"],"award-info":[{"award-number":["EF\/2025-26\/QE-04-15"]}],"id":[{"id":"https:\/\/ror.org\/040h76494","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endometrial cancer (EC) is increasingly recognized as a heterogeneous disease, yet current treatment strategies often fail to explain why tumors with similar molecular profiles respond differently or develop resistance. This gap points to regulatory mechanisms beyond static genomic alterations. Epigenetic dysregulation through DNA methylation, histone modification, and non-coding RNA (ncRNAs) networks acts as a dynamic and reversible system that governs how tumors adapt under therapeutic pressure. In EC, alterations affecting key regulators such as MLH1, PTEN, and hormone receptors directly influence sensitivity to immunotherapy, targeted therapy, and endocrine treatment, defining treatment-responsive and treatment-resistant states. These observations shift the role of epigenetics from a descriptive feature of tumor biology to a determinant of therapeutic behaviour. Epigenetic states influence immune recognition, pathway activation, and cell cycle control, thereby shaping response to chemotherapy and immune checkpoint blockade. Biomarkers derived from these alterations, including methylation signatures and circulating RNAs, offer opportunities for patient stratification and longitudinal monitoring of treatment response. Therapeutically, targeting epigenetic regulators provides a strategy to reverse resistance and restore treatment sensitivity. DNA methyltransferase and histone deacetylase inhibitors, particularly in combination with established therapies, have shown potential to enhance treatment efficacy. Emerging approaches, including locus-specific epigenetic editing and liquid biopsy\u2013guided monitoring, further support adaptive treatment strategies. Integrating epigenetic reprogramming into clinical decision-making offers a practical path toward improving treatment response and overcoming resistance in EC. Here, we propose an Epigenetic State\u2013Response Framework (ESRF) in which dynamic epigenetic states define treatment-sensitive and resistant phenotypes, map to specific therapeutic vulnerabilities, and can be actively reprogrammed to restore treatment response.<\/jats:p>","DOI":"10.3390\/ijms27104371","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T16:27:56Z","timestamp":1778776076000},"page":"4371","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Epigenetic Dysregulation to Therapeutic Reprogramming in Endometrial Cancer: A State\u2013Response Framework for Treatment Resistance"],"prefix":"10.3390","volume":"27","author":[{"given":"Manyata","family":"Srivastava","sequence":"first","affiliation":[{"name":"Translational Oncology & Women\u2019s Health, Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shishir","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1652-694X","authenticated-orcid":false,"given":"Pratik","family":"Kumar","sequence":"additional","affiliation":[{"name":"Translational Oncology & Women\u2019s Health, Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Moond","sequence":"additional","affiliation":[{"name":"Translational Oncology & Women\u2019s Health, Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Chouhan","sequence":"additional","affiliation":[{"name":"Translational Oncology & Women\u2019s Health, Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal","family":"Mann","sequence":"additional","affiliation":[{"name":"Translational Oncology & Women\u2019s Health, Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4687-1058","authenticated-orcid":false,"given":"Sarita","family":"Kumari","sequence":"additional","affiliation":[{"name":"Gynae Surgical Oncology, Max Institute of Cancer Care, Max Healthcare, Delhi 110075, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monisha","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Molecular & Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-7121","authenticated-orcid":false,"given":"Atar Singh","family":"Kushwah","sequence":"additional","affiliation":[{"name":"Translational Oncology & Women\u2019s Health, Department of Biosciences, Manipal University Jaipur, Jaipur 303007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e268","DOI":"10.1016\/S1470-2045(13)70591-6","article-title":"Classification of Endometrial Carcinoma: More than Two Types","volume":"15","author":"Murali","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Galant, N., Krawczyk, P., Monist, M., Obara, A., Gajek, \u0141., Grenda, A., Nico\u015b, M., Kalinka, E., and Milanowski, J. 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