{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:01:41Z","timestamp":1792040501602,"version":"4.4.0"},"reference-count":49,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T00:00:00Z","timestamp":1757203200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004829","name":"Science and Technology Department of Sichuan Province","doi-asserted-by":"publisher","award":["2024YFFK0365"],"award-info":[{"award-number":["2024YFFK0365"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Diminished ovarian reserve (DOR) poses significant challenges in reproductive health, with emerging evidence implicating DNA damage repair pathways. While GADD45A is a critical regulator of DNA repair, cell cycle and apoptosis, its role in DOR pathogenesis remains unexplored. We employed transcriptome sequencing, qPCR and Western Blot analyses to compare\n                    <jats:italic>GADD45A<\/jats:italic>\n                    expression in granulosa cells (GCs) between DOR patients and controls. Functional studies included\n                    <jats:italic>GADD45A<\/jats:italic>\n                    overexpression\/knockdown in human granulosa cells (KGN line) and phenotypic characterisation of\n                    <jats:italic>Gadd45a<\/jats:italic>\n                    knockout (KO) mice. Ovarian reserve parameters (follicle counts, hormone levels, oestrus cyclicity) and in\u00a0vitro fertilisation outcomes were systematically evaluated. DOR patients exhibited significant upregulation of GADD45A in GCs, concomitant with reduced FSHR and CYP19A1 expression. In\u00a0vitro experiments revealed that\n                    <jats:italic>GADD45A<\/jats:italic>\n                    overexpression disrupted both proliferation (Cell cycle analysis and EdU staining) and differentiation (Reduced CYP19A1 and FSHR expression) in GCs, while knockdown specifically impaired differentiation (Elevated CYP19A1 and FSHR expression).\n                    <jats:italic>Gadd45a<\/jats:italic>\n                    KO mice displayed hallmark DOR features: irregular oestrus cycles (Shorter oestrus), ovarian volume reduction, ovarian hormones dysregulation and decreased ovarian reserve (reduced primordial follicles and antral follicles, and increased atretic follicles). We found GADD45A was robustly expressed in the ovarian stroma and GCs of atretic follicles. KO oocytes showed compromised developmental competence with decreased two\u2010cell embryo rate in\u00a0vitro fertilisation. Our findings establish\n                    <jats:italic>GADD45A<\/jats:italic>\n                    dysregulation as a mechanistic contributor to DOR through dual impacts on granulosa cell differentiation and follicle survival. The\n                    <jats:italic>Gadd45a<\/jats:italic>\n                    KO mouse recapitulates key clinical DOR phenotypes, providing a validated model for therapeutic discovery.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.70820","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T03:51:18Z","timestamp":1757303478000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>\n                      <i>GADD45A<\/i>\n                    <\/scp>\n                    is Essential for Granulosa Cells Differentiation and Ovarian Reserve in Human and Mice"],"prefix":"10.1111","volume":"29","author":[{"given":"Juncen","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, West China Second University Hospital Sichuan University  Chengdu China"},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) Ministry of Education  Chengdu China"},{"name":"Joint Laboratory of Reproductive Medicine, SCU\u2010CUHK, Key Laboratory of Obstetric, Gynaecologic and Paediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Med\u2010X Centre for Manufacturing Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, West China Second University Hospital Sichuan University  Chengdu China"},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) Ministry of Education  Chengdu China"},{"name":"Reproductive Medical Center, Department of Obstetrics and Gynecology West China Second University Hospital, Sichuan University  Chengdu Sichuan 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