{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T19:53:42Z","timestamp":1776455622286,"version":"3.51.2"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"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. Reprod. Health"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Endometriosis is a heterogeneous gynecological disease manifesting in three distinct phenotypes: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). While Genome-Wide Association Studies (GWAS) have identified numerous susceptibility loci\u2014such as\n                      <jats:italic>WNT4<\/jats:italic>\n                      ,\n                      <jats:italic>FN1<\/jats:italic>\n                      , and\n                      <jats:italic>VEZT<\/jats:italic>\n                      \u2014the functional translation of these genetic risks into phenotype-specific pathophysiology remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This systematic review aims to analyze the differential activation and expression patterns of known endometriosis-susceptibility genes across SUP, OMA, and DIE to determine if distinct genetic signatures define each phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic search was conducted in PubMed, Scopus, and Embase up to September 2025. We included observational case-control and cohort studies comparing the mRNA or protein expression of GWAS-identified susceptibility genes in ectopic endometrial tissue, stratified by phenotype. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 15 studies involving 1,240 tissue samples were included in the final synthesis. The analysis revealed significant heterogeneity in gene activation. Genes associated with cell adhesion and invasion (e.g.,\n                      <jats:italic>FN1<\/jats:italic>\n                      ,\n                      <jats:italic>MMP2<\/jats:italic>\n                      ) were predominantly upregulated in DIE lesions (Fold Change &amp;gt; 2.5 vs. eutopic), correlating with the fibrotic nature of the disease. Conversely, OMA lesions exhibited a distinct upregulation of oxidative stress-related genes and iron metabolism regulators (e.g.,\n                      <jats:italic>HMOX1<\/jats:italic>\n                      ), likely driven by the hemoglobin-rich environment of the ovary. SUP lesions showed variable expression profiles, often characterized by acute inflammatory markers (e.g.,\n                      <jats:italic>IL-6<\/jats:italic>\n                      ,\n                      <jats:italic>COX-2<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Endometriosis phenotypes are not merely anatomical variations but represent biologically distinct entities driven by unique gene activation profiles. These findings support a move toward phenotype-specific molecular diagnostics and targeted therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/frph.2026.1749020","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T06:56:26Z","timestamp":1770706586000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Unraveling molecular heterogeneity: a systematic review of susceptibility gene profiles in ovarian, deep infiltrating, and superficial peritoneal endometriosis"],"prefix":"10.3389","volume":"8","author":[{"given":"Herbert","family":"Situmorang","sequence":"first","affiliation":[{"name":"Kintani Reproductive Health Unit, Dr Cipto Mangunkusumo National Hospital","place":["Jakarta, Indonesia"]},{"name":"Department of Obstetrics and Gynecology, Dr Cipto Mangunkusumo National Hospital, Medical Faculty Universitas Indonesia","place":["Jakarta, Indonesia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cepi Teguh","family":"Pramayadi","sequence":"additional","affiliation":[{"name":"Kintani Reproductive Health Unit, Dr Cipto Mangunkusumo National Hospital","place":["Jakarta, Indonesia"]},{"name":"Department of Obstetrics and Gynecology, Dr Cipto Mangunkusumo National Hospital, Medical Faculty Universitas Indonesia","place":["Jakarta, Indonesia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riyan Hari","family":"Kurniawan","sequence":"additional","affiliation":[{"name":"Kintani Reproductive Health Unit, Dr Cipto Mangunkusumo National Hospital","place":["Jakarta, Indonesia"]},{"name":"Department of Obstetrics and Gynecology, Dr Cipto Mangunkusumo National Hospital, Medical Faculty Universitas Indonesia","place":["Jakarta, Indonesia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Dwi","family":"Priangga","sequence":"additional","affiliation":[{"name":"Kintani Reproductive Health Unit, Dr Cipto Mangunkusumo National Hospital","place":["Jakarta, Indonesia"]},{"name":"Department of Obstetrics and Gynecology, Dr Cipto Mangunkusumo National Hospital, Medical Faculty Universitas Indonesia","place":["Jakarta, Indonesia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Syauqi","family":"Mirza","sequence":"additional","affiliation":[{"name":"Kintani Reproductive Health Unit, Dr Cipto Mangunkusumo National Hospital","place":["Jakarta, Indonesia"]},{"name":"Department of Obstetrics and Gynecology, Dr Cipto Mangunkusumo National Hospital, Medical Faculty Universitas Indonesia","place":["Jakarta, Indonesia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eka Rusdianto","family":"Gunardi","sequence":"additional","affiliation":[{"name":"Kintani Reproductive Health Unit, Dr Cipto Mangunkusumo National Hospital","place":["Jakarta, Indonesia"]},{"name":"Department of Obstetrics and Gynecology, Dr Cipto Mangunkusumo 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