{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:37Z","timestamp":1785407497661,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"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":["32260162"],"award-info":[{"award-number":["32260162"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32260162"],"award-info":[{"award-number":["32260162"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Jiangxi Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["20242BAB25499"],"award-info":[{"award-number":["20242BAB25499"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Inflammatory bowel diseases, particularly ulcerative colitis (UC), are chronic relapsing inflammatory disorders with limited therapeutic options. The zinc-finger transcription factor ZBTB4 has been implicated in the initiation and progression of cancer, but its role in UC remains unknown. Here, we found that ZBTB4 deficiency exacerbates dextran sulfate sodium (DSS)-induced colitis in C57BL\/6J male mice. Compared with the wild type, ZBTB4 deficiency increases weight loss, colon shortening and proinflammatory cytokine production. RNA-seq analysis revealed that ZBTB4 deficiency enhances Serpine1 expression and activates the NF-\u03baB pathway. NF-\u03baB inhibition by JSH-23 alleviated the effect of ZBTB4 deficiency on DSS-induced colitis. These results imply the protective role of ZBTB4 in UC. Through an integrated drug screening, we identified a natural sesquiterpene lactone, handelin, as a potential compound to enhance ZBTB4 expression in NCM460 cells. Handelin administration relieved colitis in wild-type mice but produced no effect in ZBTB4 knockout mice, demonstrating that its anti-colitic effect depends on ZBTB4 expression. Collectively, our results indicate the key role of ZBTB4 in UC and ZBTB4 agonists may serve as a novel approach for UC treatments.<\/jats:p>","DOI":"10.3390\/cells15100929","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"929","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ZBTB4 Deficiency Exacerbates DSS-Induced Colitis Through Activating NF-\u03baB Pathway"],"prefix":"10.3390","volume":"15","author":[{"given":"Xinyi","family":"Peng","sequence":"first","affiliation":[{"name":"The Center for Translational Medicine, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genglin","family":"Guo","sequence":"additional","affiliation":[{"name":"The Center for Translational Medicine, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyu","family":"Li","sequence":"additional","affiliation":[{"name":"The Center for Translational Medicine, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyao","family":"Sun","sequence":"additional","affiliation":[{"name":"The Center for Translational Medicine, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Ouyang","sequence":"additional","affiliation":[{"name":"The Center for Translational Medicine, Yichun University, Yichun 336000, China"},{"name":"The Department of Biochemistry, School of Basic Medical Sciences, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9000-371X","authenticated-orcid":false,"given":"Jiajun","family":"Cui","sequence":"additional","affiliation":[{"name":"The Center for Translational Medicine, Yichun University, Yichun 336000, China"},{"name":"The Department of Biochemistry, School of Basic Medical Sciences, Yichun University, Yichun 336000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev-pathol-012615-044152","article-title":"Genetics and Pathogenesis of Inflammatory Bowel Disease","volume":"11","author":"Liu","year":"2016","journal-title":"Annu. Rev. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1053\/j.gastro.2011.10.001","article-title":"Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review","volume":"142","author":"Molodecky","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1056\/NEJMra020831","article-title":"Inflammatory bowel disease","volume":"347","author":"Podolsky","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.14309\/ajg.0000000000003463","article-title":"ACG Clinical Guideline Update: Ulcerative Colitis in Adults","volume":"120","author":"Rubin","year":"2025","journal-title":"Am. J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/S0140-6736(16)32126-2","article-title":"Ulcerative colitis","volume":"389","author":"Ungaro","year":"2017","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"493012","DOI":"10.1155\/2015\/493012","article-title":"Inflammatory Bowel Disease: An Overview of Immune Mechanisms and Biological Treatments","volume":"2015","author":"Garcia","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3358","DOI":"10.4161\/cc.21277","article-title":"The BTB-ZF transcription factors","volume":"11","author":"Siggs","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/febs.16905","article-title":"Dimerization choice and alternative functions of ZBTB transcription factors","volume":"291","author":"Barakat","year":"2024","journal-title":"FEBS J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cheng, Z.Y., He, T.T., Gao, X.M., Zhao, Y., and Wang, J. (2021). ZBTB Transcription Factors: Key Regulators of the Development, Differentiation and Effector Function of T Cells. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.713294"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12964-017-0178-x","article-title":"Kaiso differentially regulates components of the Notch signaling pathway in intestinal cells","volume":"15","author":"Robinson","year":"2017","journal-title":"Cell Commun. Signal"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1038\/mi.2017.17","article-title":"The transcriptional repressor HIC1 regulates intestinal immune homeostasis","volume":"10","author":"Burrows","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gao, X., Shen, X., Liu, K., Lu, C., Fan, Y., Xu, Q., Meng, X., Hong, S., Huang, Z., and Liu, X. (2022). The Transcription Factor ThPOK Regulates ILC3 Lineage Homeostasis and Function During Intestinal Infection. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.939033"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1158\/1535-7163.MCT-12-0181","article-title":"Induction of the transcriptional repressor ZBTB4 in prostate cancer cells by drug-induced targeting of microRNA-17-92\/106b-25 clusters","volume":"11","author":"Kim","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"155397","DOI":"10.1016\/j.cyto.2020.155397","article-title":"Suppression of lncRNA MALAT1 reduces pro-inflammatory cytokines production by regulating miR-150-5p\/ZBTB4 axis through JAK\/STAT signal pathway in systemic juvenile idiopathic arthritis","volume":"138","author":"Jiang","year":"2021","journal-title":"Cytokine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.cell.2019.10.027","article-title":"Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways","volume":"179","author":"Huang","year":"2019","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15.25.1","DOI":"10.1002\/0471142735.im1525s104","article-title":"Dextran sulfate sodium (DSS)-induced colitis in mice","volume":"104","author":"Chassaing","year":"2014","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114625","DOI":"10.1016\/j.ecoenv.2023.114625","article-title":"Exposure to Di-(2-Ethylhexyl) phthalate drives ovarian dysfunction by inducing granulosa cell pyroptosis via the SLC39A5\/NF-\u03baB\/NLRP3 axis","volume":"252","author":"Sun","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3306559","DOI":"10.1155\/2022\/3306559","article-title":"Visfatin Amplifies Cardiac Inflammation and Aggravates Cardiac Injury via the NF-\u03baB p65 Signaling Pathway in LPS-Treated Mice","volume":"2022","author":"Hu","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/jcsm.13381","article-title":"Handelin alleviates cachexia- and aging-induced skeletal muscle atrophy by improving protein homeostasis and inhibiting inflammation","volume":"15","author":"Zhang","year":"2024","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrgastro.2015.186","article-title":"Immunopathogenesis of IBD: Current state of the art","volume":"13","author":"Fiocchi","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.crohns.2012.08.003","article-title":"Plasminogen activator inhibitor-1 is increased in colonic epithelial cells from patients with colitis-associated cancer","volume":"7","author":"Gillespie","year":"2013","journal-title":"J. Crohns Colitis"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nature06005","article-title":"Unravelling the pathogenesis of inflammatory bowel disease","volume":"448","author":"Xavier","year":"2007","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.tips.2024.08.003","article-title":"Ulcerative colitis: Clinical biomarkers, therapeutic targets, and emerging treatments","volume":"45","author":"Wangchuk","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S33","DOI":"10.1038\/d41586-018-07276-2","article-title":"Ulcerative colitis: Towards remission","volume":"563","author":"Eisenstein","year":"2018","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1093\/ibd\/izz149","article-title":"Inflammation and Inflammatory Cytokine Contribute to the Initiation and Development of Ulcerative Colitis and Its Associated Cancer","volume":"25","author":"Yao","year":"2019","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1038\/s41467-022-33331-8","article-title":"Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy","volume":"13","author":"Pavlidis","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1128\/MCB.18.7.4235","article-title":"BAZF, a novel Bcl6 homolog, functions as a transcriptional repressor","volume":"18","author":"Okabe","year":"1998","journal-title":"Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1084\/jem.20112084","article-title":"ZBTB1 is a determinant of lymphoid development","volume":"209","author":"Siggs","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00705-020-04854-6","article-title":"ZBTB gene expression in HIV patients: A possible new molecular mechanism of viral control","volume":"166","year":"2021","journal-title":"Arch. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41413-025-00414-3","article-title":"LATS1-modulated ZBTB20 perturbing cartilage matrix homeostasis contributes to early-stage osteoarthritis","volume":"13","author":"Hao","year":"2025","journal-title":"Bone Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5091","DOI":"10.1038\/s41388-019-0777-7","article-title":"Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma","volume":"38","author":"Short","year":"2019","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yang, Z., Chen, F., Wang, F., Chen, X., Zheng, B., Liao, X., Deng, Z., Ruan, X., Ning, J., and Li, Q. (2023). Identification of ZBTB4 as an immunological biomarker that can inhibit the proliferation and invasion of pancreatic cancer. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10749-x"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"121872","DOI":"10.1016\/j.lfs.2023.121872","article-title":"Hypoxia derived exosomes promote the proliferation and metastasis of colorectal cancer through the regulation of HIF-1alpha\/miR-4299\/ZBTB4","volume":"329","author":"Wu","year":"2023","journal-title":"Life Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.arcmed.2008.08.001","article-title":"NF-kappaB p65 antisense oligonucleotides may serve as a novel molecular approach for the treatment of patients with ulcerative colitis","volume":"39","author":"Li","year":"2008","journal-title":"Arch. Med. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41577-024-01008-6","article-title":"Strategies for targeting cytokines in inflammatory bowel disease","volume":"24","author":"Neurath","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12943-024-01985-1","article-title":"Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-\u03baB p65 nuclear translocation","volume":"23","author":"Zhang","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"137116","DOI":"10.1016\/j.jhazmat.2025.137116","article-title":"SO2 derivatives impair ovarian function by inhibiting Serpine1\/NF-\u03baB pathway-mediated ovarian granulosa cell survival","volume":"487","author":"Wu","year":"2025","journal-title":"J. Hazard. Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.7150\/ijbs.75890","article-title":"Plasminogen Activator Inhibitor-1 Potentiates Neutrophil Infiltration and Tissue Injury in Colitis","volume":"19","author":"Wang","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.cell.2004.07.013","article-title":"IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer","volume":"118","author":"Greten","year":"2004","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"a000141","DOI":"10.1101\/cshperspect.a000141","article-title":"NF-kappaB as a critical link between inflammation and cancer","volume":"1","author":"Karin","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9621","DOI":"10.2147\/CMAR.S266529","article-title":"Expression of Zinc Finger and BTB Domain-Containing 4 in Colorectal Cancer and Its Clinical Significance","volume":"12","author":"Xiang","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Bailly, C. (2025). Biological and Medicinal Properties of Chrysanthemum boreale Makino and Its Bioactive Products. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26135956"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"121388","DOI":"10.1016\/j.lfs.2023.121388","article-title":"The novel TAK1 inhibitor handelin inhibits NF-\u03baB and AP-1 activity to alleviate elastase-induced emphysema in mice","volume":"319","author":"Yun","year":"2023","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1021\/np4009877","article-title":"Suppression of inflammatory responses by handelin, a guaianolide dimer from Chrysanthemum boreale, via downregulation of NF-\u03baB signaling and pro-inflammatory cytokine production","volume":"77","author":"Pyee","year":"2014","journal-title":"J. Nat. Prod."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/10\/929\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:20:14Z","timestamp":1779697214000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/10\/929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cells15100929"],"URL":"https:\/\/doi.org\/10.3390\/cells15100929","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]}}}