{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:36:55Z","timestamp":1791895015467,"version":"4.3.4"},"reference-count":321,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endometriosis is traditionally conceptualized as a pelvic lesion\u2013centered disease; however, mounting evidence indicates it is a chronic, systemic, and multifactorial inflammatory disorder. This review examines the molecular dialog between ectopic endometrial tissue, the immune system, and peripheral organs, highlighting mechanisms that underlie disease chronicity, symptom variability, and therapeutic resistance. Ectopic endometrium exhibits distinct transcriptomic and epigenetic signatures, disrupted hormonal signaling, and a pro-inflammatory microenvironment characterized by inflammatory mediators, prostaglandins, and matrix metalloproteinases. Immune-endometrial crosstalk fosters immune evasion through altered cytokine profiles, extracellular vesicles, immune checkpoint molecules, and immunomodulatory microRNAs, enabling lesion persistence. Beyond the pelvis, systemic low-grade inflammation, circulating cytokines, and microRNAs reflect a molecular spillover that contributes to chronic pain, fatigue, hypothalamic\u2013pituitary\u2013adrenal axis dysregulation, and emerging gut\u2013endometrium interactions. Furthermore, circulating biomarkers\u2014including microRNAs, lncRNAs, extracellular vesicles, and proteomic signatures\u2014offer potential for early diagnosis, patient stratification, and monitoring of therapeutic responses. Conventional hormonal therapies demonstrate limited efficacy, whereas novel molecular targets and delivery systems, including angiogenesis inhibitors, immune modulators, epigenetic regulators, and nanotherapeutics, show promise for precision intervention. A systems medicine framework, integrating multi-omics analyses and network-based approaches, supports reconceptualizing endometriosis as a systemic inflammatory condition with gynecologic manifestations. This perspective emphasizes the need for interdisciplinary collaboration to advance diagnostics, therapeutics, and individualized patient care, ultimately moving beyond a lesion-centered paradigm toward a molecularly informed, holistic understanding of endometriosis.<\/jats:p>","DOI":"10.3390\/ijms27020908","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:39:37Z","timestamp":1768563577000},"page":"908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Endometriosis as a Systemic and Complex Disease: Toward Phenotype-Based Classification and Personalized Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3641-1501","authenticated-orcid":false,"given":"Daniel","family":"Simancas-Racines","sequence":"first","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"},{"name":"Facultad de Salud y Bienestar, Pontificia Universidad Cat\u00f3lica del Ecuador, Quito 170143, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9670-6376","authenticated-orcid":false,"given":"Emilia","family":"Jim\u00e9nez-Flores","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"},{"name":"Centro de Investigaci\u00f3n en Salud P\u00fablica y Epidemiolog\u00eda Cl\u00ednica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9550-2772","authenticated-orcid":false,"given":"Martha","family":"Montalvan","sequence":"additional","affiliation":[{"name":"Escuela de Medicina, Universidad Esp\u00edritu Santo, Samborond\u00f3n 0901952, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4909-2925","authenticated-orcid":false,"given":"Raquel","family":"Horowitz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Geriatrics Division, Montefiore Medical Center, Bronx, NY 10467, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5877-4107","authenticated-orcid":false,"given":"Valeria","family":"Araujo","sequence":"additional","affiliation":[{"name":"Facultad de Salud y Bienestar, Pontificia Universidad Cat\u00f3lica del Ecuador, Quito 170143, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4234-5524","authenticated-orcid":false,"given":"Claudia","family":"Reytor-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud y Bienestar Humano, Universidad Tecnol\u00f3gica Indoam\u00e9rica, Ambato 180150, Ecuador"},{"name":"Escuela de Medicina, Pontificia Universidad Cat\u00f3lica del Ecuador, Santo Domingo 230203, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Czubak, P., Herda, K., Niewiadomska, I., Putowski, L., \u0141a\u0144cut, M., and Mas\u0142yk, M. 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