{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T02:30:00Z","timestamp":1786329000944,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":66,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82170784, No. 82370775, and No.82570905"],"award-info":[{"award-number":["No. 82170784, No. 82370775, and No.82570905"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Benign prostatic hyperplasia (BPH) is a common chronic disease among elderly men, and its etiology remains unclear. This study aimed to investigate the expression, biological function, and underlying mechanism of JMJD3 in BPH. Here, we identified that JMJD3 is a crucial driver of BPH progression. In this work, both scRNA and bulk sequencing data revealed that JMJD3 is upregulated in BPH, which was further validated in prostate tissues from BPH patients. Functionally, Overexpressing JMJD3 could promote cell proliferation and cell cycles in WPMY-1 and RWPE-1 cells, respectively. Whereas, blocking JMJD3 with GSK-J4 or siRNA may induce cell apoptosis, and inhibit cell proliferation and cell cycles in BPH-1 cells. Furthermore, inhibition of JMJD3 with GSK-J4 could alleviate both testosterone and lipopolysaccharide (LPS) induced BPH in vivo. Mechanistically, JMJD3 demethylates H3K27me3 at the promoter of TGF-\u03b21 to promote its expression and then promotes disease progression in BPH. In summary, our findings illustrate JMJD3\u2019s contribution to BPH progression and offer a potential JMJD3-targeted therapy for BPH.<\/jats:p>","DOI":"10.1038\/s41419-026-08967-9","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T01:15:21Z","timestamp":1780622121000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["JMJD3 modulates benign prostatic hyperplasia through epigenetic regulation of TGF-\u03b21"],"prefix":"10.1038","volume":"17","author":[{"given":"Bo","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinze","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjing","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5024-2841","authenticated-orcid":false,"given":"Qiyou","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjiang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxing","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Ran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-8299","authenticated-orcid":false,"given":"Dehong","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8170-5587","authenticated-orcid":false,"given":"Qiang","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7597-6241","authenticated-orcid":false,"given":"Liangren","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"8967_CR1","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.eururo.2024.04.031","volume":"86","author":"M Creta","year":"2024","unstructured":"Creta M, Russo GI, Bhojani N, Drake MJ, Gratzke C, Peyronnet B, et al. Bladder outlet obstruction relief and symptom improvement following medical and surgical therapies for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review. Eur Urol. 2024;86:315\u201326.","journal-title":"Eur Urol"},{"key":"8967_CR2","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/s41391-023-00700-3","volume":"27","author":"S Gravas","year":"2024","unstructured":"Gravas S, Malde S, Cornu JN, Gacci M, Gratzke C, Herrmann TRW, et al. From BPH to male LUTS: a 20-year journey of the EAU guidelines. Prostate Cancer Prostatic Dis. 2024;27:48\u201353.","journal-title":"Prostate Cancer Prostatic Dis"},{"key":"8967_CR3","doi-asserted-by":"publisher","first-page":"135","DOI":"10.4103\/aja202357","volume":"26","author":"GM Busetto","year":"2024","unstructured":"Busetto GM, Checchia A, Recchia M, Tocci E, Falagario UG, Annunziata G, et al. Minimally invasive surgical therapies (MISTs) for lower urinary tract symptoms (LUTS): promise or panacea? Asian J Androl. 2024;26:135\u201343.","journal-title":"Asian J Androl"},{"key":"8967_CR4","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s10020-023-00734-2","volume":"29","author":"S Shan","year":"2023","unstructured":"Shan S, Su M, Li Y, Wang Z, Liu D, Zhou Y, et al. Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-beta-catenin signaling axis and static & dynamic dual roles. Mol Med. 2023;29:139.","journal-title":"Mol Med"},{"key":"8967_CR5","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1111\/iju.15518","volume":"31","author":"S Inamura","year":"2024","unstructured":"Inamura S, Terada N. Chronic inflammation in benign prostatic hyperplasia: Pathophysiology and treatment options. Int J Urol. 2024;31:968\u201374.","journal-title":"Int J Urol"},{"key":"8967_CR6","doi-asserted-by":"publisher","first-page":"322","DOI":"10.21037\/tau.2020.02.08","volume":"9","author":"B Chen","year":"2020","unstructured":"Chen B, Cao D, Chen Z, Huang Y, Lin T, Ai J, et al. Estrogen regulates the proliferation and inflammatory expression of primary stromal cell in benign prostatic hyperplasia. Transl Androl Urol. 2020;9:322\u201331.","journal-title":"Transl Androl Urol"},{"key":"8967_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.31","volume":"2","author":"B Chughtai","year":"2016","unstructured":"Chughtai B, Forde JC, Thomas DD, Laor L, Hossack T, Woo HH, et al. Benign prostatic hyperplasia. Nat Rev Dis Primers. 2016;2:16031.","journal-title":"Nat Rev Dis Primers"},{"key":"8967_CR8","doi-asserted-by":"publisher","first-page":"2387","DOI":"10.1056\/NEJMoa030656","volume":"349","author":"JD McConnell","year":"2003","unstructured":"McConnell JD, Roehrborn CG, Bautista OM, Andriole GL Jr, Dixon CM, Kusek JW, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387\u201398.","journal-title":"N Engl J Med"},{"key":"8967_CR9","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1007\/s13238-019-0653-9","volume":"10","author":"X Zhang","year":"2019","unstructured":"Zhang X, Liu L, Yuan X, Wei Y, Wei X. JMJD3 in the regulation of human diseases. Protein Cell. 2019;10:864\u201382.","journal-title":"Protein Cell"},{"key":"8967_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110719","volume":"39","author":"K Ming-Chin Lee","year":"2022","unstructured":"Ming-Chin Lee K, Achuthan AA, De Souza DP, Lupancu TJ, Binger KJ, Lee MKS, et al. Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization. Cell Rep. 2022;39:110719.","journal-title":"Cell Rep"},{"key":"8967_CR11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/s41368-022-00190-4","volume":"14","author":"Y Jin","year":"2022","unstructured":"Jin Y, Liu Z, Li Z, Li H, Zhu C, Li R, et al. Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1. Int J Oral Sci. 2022;14:34.","journal-title":"Int J Oral Sci"},{"key":"8967_CR12","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1016\/j.cell.2016.04.012","volume":"165","author":"C Merkwirth","year":"2016","unstructured":"Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Jordan SD, Quiros PM, et al. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell. 2016;165:1209\u201323.","journal-title":"Cell"},{"key":"8967_CR13","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1016\/j.cmet.2019.03.009","volume":"29","author":"C Ling","year":"2019","unstructured":"Ling C, Ronn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 2019;29:1028\u201344.","journal-title":"Cell Metab"},{"key":"8967_CR14","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41576-022-00468-7","volume":"23","author":"G Millan-Zambrano","year":"2022","unstructured":"Millan-Zambrano G, Burton A, Bannister AJ, Schneider R. Histone post-translational modifications - cause and consequence of genome function. Nat Rev Genet. 2022;23:563\u201380.","journal-title":"Nat Rev Genet"},{"key":"8967_CR15","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba0647","volume":"6","author":"C Wu","year":"2020","unstructured":"Wu C, Chen W, He J, Jin S, Liu Y, Yi Y, et al. Interplay of m(6)A and H3K27 trimethylation restrains inflammation during bacterial infection. Sci Adv. 2020;6:eaba0647.","journal-title":"Sci Adv"},{"key":"8967_CR16","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-022-01305-8","volume":"14","author":"J Abu-Hanna","year":"2022","unstructured":"Abu-Hanna J, Patel JA, Anastasakis E, Cohen R, Clapp LH, Loizidou M, et al. Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature. Clin Epigenetics. 2022;14:98.","journal-title":"Clin Epigenetics"},{"key":"8967_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2023.103511","volume":"23","author":"V Liedtke","year":"2024","unstructured":"Liedtke V, Stockle M, Junker K, Roggenbuck D. Benign prostatic hyperplasia\u2014a novel autoimmune disease with a potential therapy consequence? Autoimmun Rev. 2024;23:103511.","journal-title":"Autoimmun Rev"},{"key":"8967_CR18","first-page":"30","volume":"11","author":"SY Wang","year":"2024","unstructured":"Wang SY, Cai Y, Hu X, Li F, Qian XH, Xia LY, et al. P. gingivalis in oral-prostate axis exacerbates benign prostatic hyperplasia via IL-6\/IL-6R pathway. Mil Med Res. 2024;11:30.","journal-title":"Mil Med Res"},{"key":"8967_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29719-1","volume":"13","author":"RE Vickman","year":"2022","unstructured":"Vickman RE, Aaron-Brooks L, Zhang R, Lanman NA, Lapin B, Gil V, et al. TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease. Nat Commun. 2022;13:2133.","journal-title":"Nat Commun"},{"key":"8967_CR20","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.eururo.2014.06.026","volume":"66","author":"AR Zlotta","year":"2014","unstructured":"Zlotta AR, Egawa S, Pushkar D, Govorov A, Kimura T, Kido M, et al. Prevalence of inflammation and benign prostatic hyperplasia on autopsy in Asian and Caucasian men. Eur Urol. 2014;66:619\u201322.","journal-title":"Eur Urol"},{"key":"8967_CR21","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1002\/pros.21027","volume":"69","author":"G Robert","year":"2009","unstructured":"Robert G, Descazeaud A, Nicolaiew N, Terry S, Sirab N, Vacherot F, et al. Inflammation in benign prostatic hyperplasia: a 282-patients\u2019 immunohistochemical analysis. Prostate. 2009;69:1774\u201380.","journal-title":"Prostate"},{"key":"8967_CR22","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1016\/j.eururo.2007.11.026","volume":"54","author":"JC Nickel","year":"2008","unstructured":"Nickel JC, Roehrborn CG, O\u2019Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol. 2008;54:1379\u201384.","journal-title":"Eur Urol"},{"key":"8967_CR23","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/nature11262","volume":"488","author":"L Kruidenier","year":"2012","unstructured":"Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012;488:404\u20138.","journal-title":"Nature"},{"key":"8967_CR24","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1038\/s41423-022-00919-5","volume":"19","author":"CO Audu","year":"2022","unstructured":"Audu CO, Melvin WJ, Joshi AD, Wolf SJ, Moon JY, Davis FM, et al. Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair. Cell Mol Immunol. 2022;19:1251\u201362.","journal-title":"Cell Mol Immunol"},{"key":"8967_CR25","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","volume":"9","author":"Z Deng","year":"2024","unstructured":"Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, et al. TGF-beta signaling in health, disease, and therapeutics. Signal Transduct Target Ther. 2024;9:61.","journal-title":"Signal Transduct Target Ther"},{"key":"8967_CR26","doi-asserted-by":"publisher","first-page":"6200","DOI":"10.1016\/j.cell.2024.08.036","volume":"187","author":"M Jin","year":"2024","unstructured":"Jin M, Seed RI, Cai G, Shing T, Wang L, Ito S, et al. Dynamic allostery drives autocrine and paracrine TGF-beta signaling. Cell. 2024;187:6200\u201319 e23.","journal-title":"Cell"},{"key":"8967_CR27","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/s41423-023-01036-7","volume":"20","author":"J Wang","year":"2023","unstructured":"Wang J, Zhao X, Wan YY. Intricacies of TGF-beta signaling in Treg and Th17 cell biology. Cell Mol Immunol. 2023;20:1002\u201322.","journal-title":"Cell Mol Immunol"},{"key":"8967_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.semcancer.2024.04.001","volume":"101","author":"YE Zhang","year":"2024","unstructured":"Zhang YE, Stuelten CH. Alternative splicing in EMT and TGF-beta signaling during cancer progression. Semin Cancer Biol. 2024;101:1\u201311.","journal-title":"Semin Cancer Biol"},{"key":"8967_CR29","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.919103","volume":"13","author":"P Xiang","year":"2022","unstructured":"Xiang P, Du Z, Wang M, Liu D, Yan W, Hao Y, et al. RNA sequencing and integrative analysis reveal pathways and hub genes associated with TGFbeta1 stimulation on prostatic stromal cells. Front Genet. 2022;13:919103.","journal-title":"Front Genet"},{"key":"8967_CR30","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1016\/j.jsps.2023.05.004","volume":"31","author":"CM Liu","year":"2023","unstructured":"Liu CM, Shao Z, Chen X, Chen H, Su M, Zhang Z, et al. Neferine attenuates development of testosterone-induced benign prostatic hyperplasia in mice by regulating androgen and TGF-beta\/Smad signaling pathways. Saudi Pharm J. 2023;31:1219\u201328.","journal-title":"Saudi Pharm J"},{"key":"8967_CR31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2025.119995","volume":"349","author":"L Chen","year":"2025","unstructured":"Chen L, Lin M, Wang Y, Wang X, Qi C, Fan R, et al. Taraxacum mongolicum total triterpenoids and taraxasterol ameliorate benign prostatic hyperplasia by inhibiting androgen levels, inflammatory responses, and epithelial-mesenchymal transition via the TGFbeta1\/Smad signalling pathway. J Ethnopharmacol. 2025;349:119995.","journal-title":"J Ethnopharmacol"},{"key":"8967_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04979-3","volume":"13","author":"Y Yang","year":"2022","unstructured":"Yang Y, Sheng J, Hu S, Cui Y, Xiao J, Yu W, et al. Estrogen and G protein-coupled estrogen receptor accelerate the progression of benign prostatic hyperplasia by inducing prostatic fibrosis. Cell Death Dis. 2022;13:533.","journal-title":"Cell Death Dis"},{"key":"8967_CR33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1002\/jcp.30529","volume":"237","author":"S Aashaq","year":"2022","unstructured":"Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-beta signaling: a recap of SMAD-independent and SMAD-dependent pathways. J Cell Physiol. 2022;237:59\u201385.","journal-title":"J Cell Physiol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08967-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08967-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08967-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T02:13:40Z","timestamp":1786328020000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08967-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,5]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8967"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08967-9","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,5]]},"assertion":[{"value":"5 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This investigation was approved by the Ethics Review Committee of West China Hospital, and informed consent was obtained from all patients (No. 20230308039 and No. 2022-1700).","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"701"}}