{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:56:12Z","timestamp":1781690172396,"version":"3.54.5"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi province","doi-asserted-by":"publisher","award":["20252BAC240109"],"award-info":[{"award-number":["20252BAC240109"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi province","doi-asserted-by":"publisher","award":["20232BAB206022"],"award-info":[{"award-number":["20232BAB206022"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82560298"],"award-info":[{"award-number":["82560298"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260293"],"award-info":[{"award-number":["82260293"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Premature ovarian insufficiency (POI), a major cause of female infertility, is a condition where the ovaries lose their function before the age of 40. Growing evidence suggests that lysine acetyltransferase 2A (KAT2A) has been identified as a critical factor for mammalian development and the maintenance of genome stability and is associated with aging. However, the function of KAT2A in POI remains unclear. Our objective was to elucidate the role of KAT2A in the progression of POI and the intricate underlying mechanisms involved. KAT2A expression was significantly increased in human granulosa cells (hGCs) isolated from POI patients, as well as in the ovaries of aged mice. KAT2A overexpression aggravated estrous cyclicity irregularity, hormonal imbalances, follicular development disorders, increased follicular atresia, and decreased ovarian reserve in mice. Meanwhile, KAT2A overexpression exacerbates reactive oxygen species\u2013induced cellular apoptosis in mouse GCs. Mechanistically, gene set enrichment analysis revealed that KAT2A upregulation significantly enriched apoptosis and p38 mitogen-activated protein kinase (MAPK) signaling pathway. Using a p38\/MAPK-specific inhibitor in rescue experiments confirmed that the inhibition of p38\/MAPK is essential for KAT2A-mediated ovarian dysfunction. In summary, the current study elucidated the molecular network of KAT2A-p38\/MAPK in pathogenesis of POI, KAT2A promotes the progression of premature ovarian insufficiency (POI) via the p38\/MAPK signaling pathway, thereby implying it to be a potential therapeutic target for female reproductive aging.<\/jats:p>","DOI":"10.1093\/biolre\/ioag038","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T12:54:12Z","timestamp":1771505652000},"page":"1909-1923","source":"Crossref","is-referenced-by-count":0,"title":["KAT2A contributes to premature ovarian insufficiency by activating the P38\/MAPK signaling pathway to drive granulosa cell dysfunction"],"prefix":"10.1093","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6921-829X","authenticated-orcid":false,"given":"Jia","family":"Li","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfei","family":"Huang","sequence":"additional","affiliation":[{"name":"Queen Mary School, Jiangxi Medical College, Nanchang University , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Yu","sequence":"additional","affiliation":[{"name":"HuanKui Academy, Nanchang University , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aixia","family":"Xu","sequence":"additional","affiliation":[{"name":"JiangXi Maternal and Child Health Hospital, Maternal and Child Heath Hospital of Nanchang Medical College , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7146-6121","authenticated-orcid":false,"given":"Tao","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Zheng","sequence":"additional","affiliation":[{"name":"HuanKui Academy, Nanchang University , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Le","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xu","sequence":"additional","affiliation":[{"name":"JiangXi Maternal and Child Health Hospital, Maternal and Child Heath Hospital of Nanchang Medical College , Nanchang, Jiangxi province ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"2026061705221733100_ref1","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1093\/humrep\/dew027","article-title":"ESHRE guideline: management of women with premature ovarian insufficiency","volume":"31","author":"European Society for Human R","year":"2016","journal-title":"Hum Reprod"},{"key":"2026061705221733100_ref2","doi-asserted-by":"publisher","first-page":"e077469","DOI":"10.1136\/bmj-2023-077469","article-title":"Premature ovarian insufficiency","volume":"384","author":"Nash","year":"2024","journal-title":"BMJ"},{"key":"2026061705221733100_ref3","doi-asserted-by":"publisher","first-page":"hoae065","DOI":"10.1093\/hropen\/hoae065","article-title":"Evidence-based guideline: premature ovarian insufficiency","volume":"2024","author":"Panay","year":"2024","journal-title":"Hum Reprod Open"},{"key":"2026061705221733100_ref4","doi-asserted-by":"publisher","first-page":"114941","DOI":"10.1016\/j.ecoenv.2023.114941","article-title":"The ovarian-related effects of polystyrene nanoplastics on human ovarian granulosa cells and female mice","volume":"257","author":"Zeng","year":"2023","journal-title":"Ecotoxicol Environ Saf"},{"key":"2026061705221733100_ref5","doi-asserted-by":"publisher","first-page":"101431","DOI":"10.1016\/j.redox.2020.101431","article-title":"Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility","volume":"30","author":"Lin","year":"2020","journal-title":"Redox Biol"},{"key":"2026061705221733100_ref6","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.molmed.2009.06.005","article-title":"p38(MAPK): stress responses from molecular mechanisms to therapeutics","volume":"15","author":"Coulthard","year":"2009","journal-title":"Trends Mol Med"},{"key":"2026061705221733100_ref7","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.21873\/invivo.12817","article-title":"Ethyl \u03b2-Carboline-3-carboxylate increases cervical cancer cell apoptosis through ROS-p38 MAPK Signaling pathway","volume":"36","author":"Sun","year":"2022","journal-title":"In Vivo"},{"key":"2026061705221733100_ref8","doi-asserted-by":"crossref","first-page":"102561","DOI":"10.1016\/j.tice.2024.102561","article-title":"Periplaneta americana extract CII-3 triggers cell senescence through activating ROS-p38 MAPK-p53 signaling pathway in SKOV3 cells","volume":"91","author":"Tian","year":"2024","journal-title":"Tissue Cell"},{"key":"2026061705221733100_ref9","doi-asserted-by":"publisher","first-page":"31875","DOI":"10.1038\/s41598-024-83207-8","article-title":"Total glucosides of paeony ameliorates chemotherapy-induced neuropathic pain by suppressing microglia pyroptosis through the inhibition of KAT2A-mediated p38 pathway activation and succinylation","volume":"14","author":"Chen","year":"2024","journal-title":"Sci Rep"},{"key":"2026061705221733100_ref10","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1038\/s42003-025-08259-6","article-title":"AMH regulates granulosa cell function via ESR2\/p38-MAPK signaling pathway in sheep","volume":"8","author":"Xu","year":"2025","journal-title":"Commun Biol"},{"key":"2026061705221733100_ref11","doi-asserted-by":"publisher","first-page":"117944","DOI":"10.1016\/j.jep.2024.117944","article-title":"Inhibition of p38 MAPK\/NF-kappaB p65 signaling pathway activity by rare ginsenosides ameliorates cyclophosphamide-induced premature ovarian failure and KGN cell injury","volume":"326","author":"Tao","year":"2024","journal-title":"J Ethnopharmacol"},{"key":"2026061705221733100_ref12","doi-asserted-by":"publisher","first-page":"e0029923","DOI":"10.1128\/msphere.00299-23","article-title":"Histone acetyltransferase Gcn5-mediated histone H3 acetylation facilitates cryptococcal morphogenesis and sexual reproduction","volume":"8","author":"Chen","year":"2023","journal-title":"Msphere"},{"key":"2026061705221733100_ref13","doi-asserted-by":"publisher","first-page":"e48335","DOI":"10.15252\/embr.201948335","article-title":"Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB","volume":"21","author":"Wang","year":"2020","journal-title":"EMBO Rep"},{"key":"2026061705221733100_ref14","doi-asserted-by":"crossref","first-page":"123746","DOI":"10.1016\/j.lfs.2025.123746","article-title":"KAT2A-mediated H3K79 succinylation promotes ferroptosis in diabetic nephropathy by regulating SAT2","volume":"376","author":"Peng","year":"2025","journal-title":"Life Sci"},{"key":"2026061705221733100_ref15","doi-asserted-by":"publisher","first-page":"3149","DOI":"10.1007\/s10495-025-02196-9","article-title":"KAT2A alleviates the glucose starvation-induced mitochondrial oxidative stress and ferroptosis to promote colon cancer progression","volume":"30","author":"Guo","year":"2025","journal-title":"Apoptosis"},{"key":"2026061705221733100_ref16","doi-asserted-by":"publisher","first-page":"e71140","DOI":"10.1096\/fj.202502178R","article-title":"KAT2A-H3K79succ-mediated SH2B3 upregulation promotes TNBC metastasis through diminishing the ubiquitin-dependent degradation of vimentin","volume":"39","author":"Shi","year":"2025","journal-title":"FASEB J"},{"key":"2026061705221733100_ref17","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.devcel.2019.10.024","article-title":"Gcn5-mediated histone acetylation governs nucleosome dynamics in Spermiogenesis","volume":"51","author":"Luense","year":"2019","journal-title":"Dev Cell"},{"key":"2026061705221733100_ref18","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/s41419-024-06771-x","article-title":"Histone acetyltransferase Kat2a regulates ferroptosis via enhancing Tfrc and Hmox1 expression in diabetic cardiomyopathy","volume":"15","author":"Zhen","year":"2024","journal-title":"Cell Death Dis"},{"key":"2026061705221733100_ref19","doi-asserted-by":"publisher","first-page":"20220785","DOI":"10.1515\/biol-2022-0785","article-title":"KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1","volume":"19","author":"Zeng","year":"2024","journal-title":"Open Life Sci"},{"key":"2026061705221733100_ref20","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1186\/s12903-024-03951-1","article-title":"KAT2A-mediated succinylation modification of notch1 promotes the proliferation and differentiation of dental pulp stem cells by activating notch pathway","volume":"24","author":"Ye","year":"2024","journal-title":"BMC Oral Health"},{"key":"2026061705221733100_ref21","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/S1875-5364(21)60084-5","article-title":"Effects of chitooligosaccharide-zinc on the ovarian function of mice with premature ovarian failure via the SESN2\/NRF2 signaling pathway","volume":"19","author":"Li","year":"2021","journal-title":"Chin J Nat Med"},{"key":"2026061705221733100_ref22","doi-asserted-by":"publisher","first-page":"308","DOI":"10.3390\/antiox13030308","article-title":"TRIM28-mediated excessive oxidative stress induces cellular senescence in granulosa cells and contributes to premature ovarian insufficiency In vitro and In vivo","volume":"13","author":"Zhou","year":"2024","journal-title":"Antioxidants-Basel"},{"key":"2026061705221733100_ref23","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s13048-024-01348-w","article-title":"Progestin and adipoQ receptor 7 (PAQR7) mediate the anti-apoptotic effect of P4 on human granulosa cells and its deficiency reduces ovarian function in female mice","volume":"17","author":"Li","year":"2024","journal-title":"J Ovarian Res"},{"key":"2026061705221733100_ref24","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1093\/humrep\/dew027","article-title":"ESHRE guideline: management of women with premature ovarian insufficiency","volume":"31","author":"Webber","year":"2016","journal-title":"Hum Reprod"},{"key":"2026061705221733100_ref25","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1210\/endrev\/bnaf011","article-title":"Epidemiology, genetic etiology and intervention of premature ovarian insufficiency","volume":"46","author":"Guo","year":"2025","journal-title":"Endocr Rev"},{"key":"2026061705221733100_ref26","first-page":"565","article-title":"Apoptosis as a basic mechanism in the ovarian cycle - follicular atresia and luteal regression","volume":"2","author":"Palumbo","year":"1995","journal-title":"J Soc Gynecol Investig"},{"key":"2026061705221733100_ref27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/sj.cdd.4400316","article-title":"Analysis of apoptosis and expression of gene family members in the human and baboon ovary","volume":"5","author":"Kugu","year":"1998","journal-title":"Cell Death Differ"},{"key":"2026061705221733100_ref28","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.3390\/genes12121882","article-title":"DNA damage responses during the cell cycle: insights from model organisms and beyond","volume":"12","author":"Clay","year":"2021","journal-title":"Genes (Basel)"},{"key":"2026061705221733100_ref29","doi-asserted-by":"publisher","first-page":"e54181","DOI":"10.1371\/journal.pone.0054181","article-title":"BIRB796, the inhibitor of p38 mitogen-activated protein kinase, enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cells","volume":"8","author":"He","year":"2013","journal-title":"PLoS One"},{"key":"2026061705221733100_ref30","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.fertnstert.2022.04.019","article-title":"Mitochondrial dysfunction in cumulus cells is related to decreased reproductive capacity in advanced-age women","volume":"118","author":"Lu","year":"2022","journal-title":"Fertil Steril"},{"key":"2026061705221733100_ref31","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13048-024-01387-3","article-title":"Corpus luteum presence in the bovine ovary increase intrafollicular progesterone concentration: consequences in follicular cells gene expression and follicular fluid small extracellular vesicles miRNA contents","volume":"17","author":"Rosa","year":"2024","journal-title":"J Ovarian Res"},{"key":"2026061705221733100_ref32","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.18632\/aging.100418","article-title":"GSTT1 is upregulated by oxidative stress through p38-MK2 signaling pathway in human granulosa cells: possible association with mitochondrial activity","volume":"3","author":"Ito","year":"2011","journal-title":"Aging-Us"},{"key":"2026061705221733100_ref33","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1093\/humrep\/deaa077","article-title":"Metformin inhibits testosterone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK","volume":"35","author":"Jin","year":"2020","journal-title":"Hum Reprod"},{"key":"2026061705221733100_ref34","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/nrm2434","article-title":"Cytochrome c: functions beyond respiration","volume":"9","author":"Ow","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026061705221733100_ref35","doi-asserted-by":"publisher","first-page":"e0136022","DOI":"10.1128\/jvi.01360-22","article-title":"Expression ratios of the Antiapoptotic BCL2 family members dictate the selective addiction of Kaposi's sarcoma-associated herpesvirus-transformed primary effusion lymphoma cell lines to MCL1","volume":"96","author":"Dunham","year":"2022","journal-title":"J Virol"},{"key":"2026061705221733100_ref36","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1126\/science.275.5303.1129","article-title":"Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked","volume":"275","author":"Yang","year":"1997","journal-title":"Science"},{"key":"2026061705221733100_ref37","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1093\/gerona\/gly290","article-title":"Adipose tissue senescence and inflammation in aging is reversed by the young milieu","volume":"74","author":"Ghosh","year":"2019","journal-title":"J Gerontol a-Biol"},{"key":"2026061705221733100_ref38","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1083\/jcb.201708007","article-title":"Superoxide dismutases: dual roles in controlling ROS damage and regulating ROS signaling","volume":"217","author":"Wang","year":"2018","journal-title":"J Cell Biol"},{"key":"2026061705221733100_ref39","doi-asserted-by":"publisher","first-page":"148206","DOI":"10.1016\/j.brainres.2022.148206","article-title":"Sulforaphane attenuates microglia-mediated neuronal damage by down-regulating the ROS\/autophagy\/NLRP3 signal axis in fibrillar a\u03b2-activated microglia","volume":"1801","author":"Yang","year":"2023","journal-title":"Brain Res"},{"key":"2026061705221733100_ref40","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.actbio.2024.07.056","article-title":"Growth factor-loaded ovarian extracellular matrix hydrogels promote in vivo ovarian niche regeneration and enhance fertility in premature ovarian insufficiency preclinical models","volume":"186","author":"Frances-Herrero","year":"2024","journal-title":"Acta Biomater"},{"key":"2026061705221733100_ref41","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.3390\/ijms22031371","article-title":"Ovarian aging: molecular mechanisms and medical management","volume":"22","author":"Tesarik","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026061705221733100_ref42","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1186\/s12951-024-02735-7","article-title":"Polystyrene nanoplastics induce apoptosis, autophagy, and steroidogenesis disruption in granulosa cells to reduce oocyte quality and fertility by inhibiting the PI3K\/AKT pathway in female mice","volume":"22","author":"Xue","year":"2024","journal-title":"J Nanobiotechnol"},{"key":"2026061705221733100_ref43","doi-asserted-by":"publisher","first-page":"108474","DOI":"10.1016\/j.reprotox.2023.108474","article-title":"Sodium arsenite exposure enhances H3K14 acetylation and impairs male spermatogenesis in rat testes","volume":"122","author":"Li","year":"2023","journal-title":"Reprod Toxicol"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioag038\/67015286\/ioag038.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/114\/6\/1909\/67015286\/ioag038.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/114\/6\/1909\/67015286\/ioag038.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:22:25Z","timestamp":1781688145000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/114\/6\/1909\/8492927"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,20]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,2,20]]},"published-print":{"date-parts":[[2026,6,15]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioag038","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,6]]},"published":{"date-parts":[[2026,2,20]]}}}