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The placenta, which is crucial for fetal development, exhibits structural and functional changes in GDM, but the impact of these alterations on placental trophoblast function remains unclear. During their differentiation, villous cytotrophoblast display several characteristics of senescent cells; however, the role of senescence pathways in placental function remains unexplored in normoglycemic as well as GDM pregnancies. Here, we investigate placental senescence pathways utilizing term villous tissue and primary trophoblasts to assess senescence pathways and determine fetal sex\u2010based differences in normoglycemic and GDM pregnancies. Our data suggest that both p21\u2010 and p16\u2010mediated senescence pathways are activated during trophoblast differentiation and are dysregulated in the GDM placenta in a sexually dimorphic manner. We also provide evidence for increased activation of p53\u2010Lamin A\/C and p16\u2010RB pathways in trophoblasts from GDM placentas. Reduced expression of p21 and its downstream effects on GCM1 expression and \u03b2hCG secretion outline how altered physiological senescence can affect trophoblast differentiation and function. This is an important study highlighting the disruption of placental senescence pathways in pregnancies complicated by GDM.<\/jats:p>","DOI":"10.1096\/fj.202503771rr","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T10:01:12Z","timestamp":1767348072000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Differential Activation of p53\u2010Lamin A\/C and p16\u2010\n                    <scp>Rb<\/scp>\n                    \u2010Mediated Senescence Pathways in Trophoblasts From Pregnancies Complicated by Type\n                    <scp>A2<\/scp>\n                    Gestational Diabetes Mellitus"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1812-5210","authenticated-orcid":false,"given":"Leena","family":"Kadam","sequence":"first","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylee","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylia","family":"Ahuna","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole E.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Myatt","sequence":"additional","affiliation":[{"name":"Department of Obstetrics &amp; Gynecology Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-S002"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2020.108642"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2019.0247"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ogc.2009.03.003"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/14767050801929885"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2009.170928"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2008.06.031"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2007.03.027"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-1332"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2011.07.017"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-2551"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1763"},{"issue":"2","key":"e_1_2_9_14_1","first-page":"101","article-title":"Placental Pathologic Changes in Gestational Diabetes Mellitus","volume":"36","author":"Jarmuzek P.","year":"2015","journal-title":"Neuro Endocrinology Letters"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.47162\/RJME.63.1.09"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/283124"},{"key":"e_1_2_9_17_1","first-page":"4","article-title":"Study of the Ultrastructure of the Placenta in Gestational Diabetes Mellitus","volume":"11","author":"Abdelghany A.","year":"2018","journal-title":"International Journal of Anatomy Variations"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.10.005"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.repbio.2023.100734"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.019"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2022.0416"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpz052"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050110"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2010.5"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.859231"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-268276"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201592862"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123169"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0505-1"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12101812"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112183"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22084186"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147295"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2014.11.011"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2018-023014"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4004(95)90000-4"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0531-5565(03)00132-3"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.20.9363"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.2009.172890"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-789X.2008.00541.x"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.227512.113"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.3.2109"},{"issue":"5","key":"e_1_2_9_43_1","first-page":"1169","article-title":"WAF1\/CIP1 Is Induced in p53\u2010Mediated G1 Arrest and Apoptosis","volume":"54","author":"el\u2010Deiry W. 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